Naphthylenyl compounds for long-acting injectable compositions and related methods

ABSTRACT

The present invention provides compounds useful for the treatment of opioid dependence, alcohol dependence, alcohol use disorder, or the prevention of relapse to opioid dependence in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

RELATED APPLICATIONS

This application claims of benefit of U.S. provisional patentapplication Ser. No. 62/697,890, filed on Jul. 13, 2018, the contents ofwhich are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel naphthylene-containing compoundsand their use in long-acting injectable compositions. In particular,dimeric prodrugs of naltrexone are disclosed herein. The invention alsorelates to methods of use thereof.

BACKGROUND OF THE INVENTION

Opioid dependence and alcohol dependence are chronic disorders thatresult from a variety of genetic, psychological and environmentalfactors. Traditional treatment has consisted of two phases:detoxification and rehabilitation. Detoxification ameliorates thesymptoms and signs of withdrawal while rehabilitation helps the patientavoid future problems with opioids or alcohol. In the past, manyrehabilitative treatments have been psychosocial. More recently, therehas been increasing interest in medication-assisted treatment. Thesuccessful treatment of opioid dependence or alcohol dependence has manyserious challenges and complications. Patient compliance can be aparticularly difficult challenge to overcome. Accordingly, there is aneed for novel and improved therapies.

SUMMARY OF THE INVENTION

The compounds and methods described herein comprise one or more prodrugsof naltrexone. Upon administration, the compounds of the invention canbe converted in vivo to naltrexone. Following conversion, the activemoiety (i.e., naltrexone) is effective in treating subjects sufferingfrom opioid dependence or alcohol dependence or at risk of developingopioid dependence or alcohol dependence.

The invention provides prodrugs of naltrexone (NTX) having one or twomolecules of naltrexone covalently bound to a naphthalene-containingmoiety. The compounds of the invention may extend the period duringwhich the naltrexone is released and absorbed after administration tothe subject, providing a longer duration of release than othercommercially available naltrexone products, such as VIVITROL®(naltrexone for extended-release injectable suspension) or REVIA®(naltrexone hydrochloride tablets USP).

Provided herein are compounds useful for the prevention or treatment ofopioid dependence or alcohol dependence in a subject in need thereof.

In an aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound with pointsof attachment selected from the 1 and 1′ positions, the 1 and 4′positions, the 2 and 2′ positions, or the 2 and 3′ positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 1 and 1′positions, then the R groups are bound at the 2 and 2′ positions, the 3and 3′ positions, or the 4 and 4′ positions;

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 1 and 4′positions, then the R groups are bound at the 2 and 3′ positions, the 3and 2′ positions, or the 4 and 1′ positions;

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 2 and 2′positions, then the R groups are bound at the 1 and 1′ positions, the 3and 3′ positions, or the 4 and 4′ positions; or

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 2 and 3′positions, then the R groups are bound at the 1 and 4′ positions, the 3and 2′ positions, or the 4 and 1′ positions.

Examples of a compound of Formula I provided herein include a compoundof Formula Ia, Ib, Ic, or Id, or a pharmaceutically acceptable saltthereof.

In another aspect, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound with points of attachment selected from the 1 and 1′positions, the 1 and 4′ positions, the 2 and 2′ positions, or the 2 and3′ positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 1 and 1′ positions, then the R groups are boundat the 2 and 2′ positions, the 3 and 3′ positions, or the 4 and 4′positions;

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 1 and 4′ positions, then the R groups are boundat the 2 and 3′ positions, the 3 and 2′ positions, or the 4 and 1′positions;

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 2 and 2′ positions, then the R groups are boundat the 1 and 1′ positions, the 3 and 3′ positions, or the 4 and 4′positions; or

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 2 and 3′ positions, then the R groups are boundat the 1 and 4′ positions, the 3 and 2′ positions, or the 4 and 1′positions.

Examples of a compound of Formula II provided herein include a compoundof Formula IIa, IIb, IIc, or IId, or a pharmaceutically acceptable saltthereof.

Also provided herein is a pharmaceutical composition comprising acompound of Formula I or II, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

Also provided herein is a method of treating opioid dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof. In an embodiment, the opioid is an opioid agonist. In anembodiment, the opioid is morphine, fentanyl, oxymorphone,buprenorphine, hydromorphone, oxycodone, hydrocodone, diamorphine (i.e.,heroin) or the like. In another embodiment, the opioid is oxycodone ordiamorphine. In another embodiment, the opioid is buprenorphine.

Also provided herein is a method of treating alcohol dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof.

Also provided herein is a method of preventing opioid dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof. In an embodiment, the opioid is an opioid agonist. In anembodiment, the opioid is morphine, fentanyl, oxymorphone,buprenorphine, hydromorphone, oxycodone, hydrocodone, diamorphine (i.e.,heroin) or the like. In another embodiment, the opioid is oxycodone ordiamorphine. In another embodiment, the opioid is buprenorphine.

Also provided herein is a method of preventing relapse to opioiddependence in a subject in need thereof comprising administering to thesubject a compound of Formula I or II, or a pharmaceutically acceptablesalt thereof. In an embodiment, the opioid is an opioid agonist. In anembodiment, the opioid is morphine, fentanyl, oxymorphone,buprenorphine, hydromorphone, oxycodone, hydrocodone, diamorphine (i.e.,heroin) or the like. In another embodiment, the opioid is oxycodone ordiamorphine. In another embodiment, the opioid is buprenorphine.

Also provided herein is a method of preventing alcohol dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof.

Also provided herein is a method of treating alcohol use disorder in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof. In another embodiment, the alcohol use disorder is moderate tosevere alcohol use disorder.

Also provided herein is a method for the blockade of the effects ofexogenously administered opioids in a subject in need thereof comprisingadministering to the subject a compound of Formula I or II, or apharmaceutically acceptable salt thereof. In an embodiment, the opioidis an opioid agonist. In an embodiment, the opioid is morphine,fentanyl, oxymorphone, buprenorphine, hydromorphone, oxycodone,hydrocodone, diamorphine (i.e., heroin) or the like. In anotherembodiment, the opioid is oxycodone or diamorphine. In anotherembodiment, the opioid is buprenorphine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the powder x-ray diffraction (PXRD) pattern for Compound 2.

DETAILED DESCRIPTION OF THE INVENTION

One of the challenges for delivering an active pharmaceutical ingredient(API) in a long-acting injectable composition is incorporating asufficient amount of drug to maintain effective plasma levels of APIover an extended period of time (e.g., several weeks or months) whilemaintaining a total composition volume that can be readily injected, ina single injection, into a subject. This challenge becomes still moredifficult when the API is in the form of a prodrug, and thus having amolecular weight higher than the parent API. Further, thephysicochemical properties of such a prodrug (including, but not limitedto, chemical stability, physical stability, physical form andsolubility) are important to its suitability for a long-actinginjectable composition.

Such long-acting injectable compositions can be in the form of asuspension of solids in an aqueous (liquid) composition. For example, asuspension of a prodrug of an API in an aqueous composition can beprepared for a long-acting composition. In such a system, thephysicochemical properties of the prodrug, including crystallinity andsolubility of the solid material, are important to its ability todeliver drug over an extended duration and with a therapeutic plasmaconcentration. In particular, crystalline prodrugs with low aqueoussolubility are important for long-acting injectable suspensions.

Provided herein are novel compounds which are prodrugs of naltrexone(NTX) having one or two covalently-attached naltrexone molecules,related methods of treating or preventing opioid dependence or alcoholdependence by administering one or more compounds of the invention,synthetic methods for making the compounds of the invention, andpharmaceutical compositions containing compounds of the invention.

In a non-limiting aspect, the compounds of the present invention mayundergo enzyme-mediated cleavage under physiological conditions torelease the naltrexone parent drug. In one embodiment, the ultimaterelease of the naltrexone parent drug is controlled by the rate ofdissolution of a crystalline compound of Formula I or II.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±10%, including ±5%, ±1%, and ±0.1%from the specified value, as such variations are appropriate to performthe disclosed methods.

As used herein, “opioid dependence” is generally defined as a chronicbrain disease that causes compulsive drug seeking and use.

As used herein, “alcohol dependence” is generally defined as a chronicbrain disease that causes compulsive alcohol seeking and use.

As used herein, “alcohol use disorder” is generally defined asencompassing the disorders of alcohol dependence and alcohol abuse andcan be classified as mild, moderate or severe.

As used herein, the terms “treat,” “treated,” “treating,” or “treatment”includes the diminishment or alleviation of at least one symptomassociated or caused by the state, disorder or disease being treated.

As used herein, the terms “prevent,” “preventing,” or “prevention” meansno disorder or disease development if none had occurred, or no furtherdisorder or disease development if there had already been development ofthe disorder or disease. Also considered is the ability of one toprevent some or all of the symptoms associated with the disorder ordisease.

As used herein, the terms “patient,” “individual” or “subject” refer toa human.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount,” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. An appropriate therapeutic amount in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of a compound of the invention wherein the compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. The phrase “pharmaceutically acceptable salt” is notlimited to a mono, or 1:1, salt. For example, “pharmaceuticallyacceptable salt” also includes bis-salts, such as a bis-hydrochloridesalt. Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977), each of which isincorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration, such as sterilepyrogen-free water. Suitable carriers are described in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe pharmaceutical compositions is contemplated. Supplementary activecompounds can also be incorporated into the compositions. Thepharmaceutical compositions can also advantageously employ a densityenhancing agent, such as a sugar, e.g., mannitol, or sorbitol and/or atonicity adjusting agent, such as sodium chloride or glycerol. Otherpharmaceutical carriers that could be used in the pharmaceuticalcompositions provided herein also include aqueous methylcellulosesolutions, fructose solution, ethanol, or oils of animal, vegetative, orsynthetic origin. The pharmaceutically acceptable carrier may alsocontain preservatives, and buffers as are known in the art.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means a straight or branched chain hydrocarbon having thenumber of carbon atoms designated (i.e., C₁-C₄ alkyl means an alkylhaving one to four carbon atoms) and includes straight and branchedchains. Examples include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, and tert-butyl.

As used herein, the term “alkoxy,” by itself or as part of anothersubstituent, refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like.

As used herein, the term “alkylcarbonyloxy,” by itself or as part ofanother substituent, refers to the group —O—C(═O)-alkyl, wherein alkylis as defined herein. Alkylcarbonyloxy includes, by way of example,acetate, propionate, butyrate, methylbutanoate, pentanoate and the like.

As used herein, the term “halogen” alone or as part of anothersubstituent means a fluorine, chlorine, bromine, or iodine atom,preferably, fluorine, chlorine, or bromine, more preferably, fluorine orchlorine.

Compounds of the Invention

In one embodiment, a compound of the invention has the structure ofFormula I:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound with pointsof attachment selected from the 1 and 1′ positions, the 1 and 4′positions, the 2 and 2′ positions, or the 2 and 3′ positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 1 and 1′positions, then the R groups are bound at the 2 and 2′ positions, the 3and 3′ positions, or the 4 and 4′ positions;

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 1 and 4′positions, then the R groups are bound at the 2 and 3′ positions, the 3and 2′ positions, or the 4 and 1′ positions;

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 2 and 2′positions, then the R groups are bound at the 1 and 1′ positions, the 3and 3′ positions, or the 4 and 4′ positions; or

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 2 and 3′positions, then the R groups are bound at the 1 and 4′ positions, the 3and 2′ positions, or the 4 and 1′ positions.

In another embodiment of Formula I, both R groups are hydrogen.

In another embodiment of Formula I, both R groups are halogen.

In another embodiment of Formula I, both R groups are fluorine.

In another embodiment of Formula I, both R groups are chlorine.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula I, both R groups are methyl.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula I, both R groups are methoxy.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula I, both R groups are methylcarbonyloxy.

In another embodiment of Formula I, both values of z are 1.

In another embodiment of Formula I, both values of z are 2.

In another embodiment of Formula I, both values of z are 3.

In another embodiment of Formula I, both values of z are 4.

In another embodiment of Formula I, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula I, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula I, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula I, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula I, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula I, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula I, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula I, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula I, both R groups are methylcarbonyloxyand both values of z are 1.

In another embodiment of Formula I, both R groups are methylcarbonyloxyand both values of z are 2.

In another embodiment of Formula I, both R groups are methylcarbonyloxyand both values of z are 3.

In another embodiment of Formula I, both R groups are methylcarbonyloxyand both values of z are 4.

In another embodiment of Formula I, a compound of Formula Ia has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 2 and 2′ positions, the 3 and 3′ positions, or the 4 and 4′positions.

In another embodiment of Formula Ia, the R groups are bound with pointsof attachment at the 2 and 2′ positions.

In another embodiment of Formula Ia, the R groups are bound with pointsof attachment at the 3 and 3′ positions.

In another embodiment of Formula Ia, the R groups are bound with pointsof attachment at the 4 and 4′ positions.

In another embodiment of Formula Ia, both R groups are hydrogen.

In another embodiment of Formula Ia, both R groups are halogen.

In another embodiment of Formula Ia, both R groups are fluorine.

In another embodiment of Formula Ia, both R groups are chlorine.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Ia, both R groups are methyl.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula Ia, both R groups are methoxy.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula Ia, both R groups aremethylcarbonyloxy.

In another embodiment of Formula Ia, both values of z are 1.

In another embodiment of Formula Ia, both values of z are 2.

In another embodiment of Formula Ia, both values of z are 3.

In another embodiment of Formula Ia, both values of z are 4.

In another embodiment of Formula Ia, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Ia, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Ia, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ia, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula Ia, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula Ia, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula Ia, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula Ia, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula Ia, both R groups are methylcarbonyloxyand both values of z are 1.

In another embodiment of Formula Ia, both R groups are methylcarbonyloxyand both values of z are 2.

In another embodiment of Formula Ia, both R groups are methylcarbonyloxyand both values of z are 3.

In another embodiment of Formula Ia, both R groups are methylcarbonyloxyand both values of z are 4.

In another embodiment of Formula I, a compound of Formula Ib has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 1 and 1′ positions, the 3 and 3′ positions, or the 4 and 4′positions.

In another embodiment of Formula Ib, the R groups are bound with pointsof attachment at the 1 and 1′ positions.

In another embodiment of Formula Ib, the R groups are bound with pointsof attachment at the 3 and 3′ positions.

In another embodiment of Formula Ib, the R groups are bound with pointsof attachment at the 4 and 4′ positions.

In another embodiment of Formula Ib, both R groups are hydrogen.

In another embodiment of Formula Ib, both R groups are halogen.

In another embodiment of Formula Ib, both R groups are fluorine.

In another embodiment of Formula Ib, both R groups are chlorine.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Ib, both R groups are methyl.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula Ib, both R groups are methoxy.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula Ib, both R groups aremethylcarbonyloxy.

In another embodiment of Formula Ib, both values of z are 1.

In another embodiment of Formula Ib, both values of z are 2.

In another embodiment of Formula Ib, both values of z are 3.

In another embodiment of Formula Ib, both values of z are 4.

In another embodiment of Formula Ib, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Ib, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Ib, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ib, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula Ib, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula Ib, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula Ib, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula Ib, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula Ib, both R groups are methylcarbonyloxyand both values of z are 1.

In another embodiment of Formula Ib, both R groups are methylcarbonyloxyand both values of z are 2.

In another embodiment of Formula Ib, both R groups are methylcarbonyloxyand both values of z are 3.

In another embodiment of Formula Ib, both R groups are methylcarbonyloxyand both values of z are 4.

In another embodiment of Formula I, a compound of Formula Ic has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 2 and 3′ positions, the 3 and 2′ positions, or the 4 and 1′positions.

In another embodiment of Formula Ic, the R groups are bound with pointsof attachment at the 2 and 3′ positions.

In another embodiment of Formula Ic, the R groups are bound with pointsof attachment at the 3 and 2′ positions.

In another embodiment of Formula Ic, the R groups are bound with pointsof attachment at the 4 and 1′ positions.

In another embodiment of Formula Ic, both R groups are hydrogen.

In another embodiment of Formula Ic, both R groups are halogen.

In another embodiment of Formula Ic, both R groups are fluorine.

In another embodiment of Formula Ic, both R groups are chlorine.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Ic, both R groups are methyl.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula Ic, both R groups are methoxy.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula Ic, both R groups aremethylcarbonyloxy.

In another embodiment of Formula Ic, both values of z are 1.

In another embodiment of Formula Ic, both values of z are 2.

In another embodiment of Formula Ic, both values of z are 3.

In another embodiment of Formula Ic, both values of z are 4.

In another embodiment of Formula Ic, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Ic, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Ic, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ic, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula Ic, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula Ic, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula Ic, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula Ic, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula Ic, both R groups are methylcarbonyloxyand both values of z are 1.

In another embodiment of Formula Ic, both R groups are methylcarbonyloxyand both values of z are 2.

In another embodiment of Formula Ic, both R groups are methylcarbonyloxyand both values of z are 3.

In another embodiment of Formula Ic, both R groups are methylcarbonyloxyand both values of z are 4.

In another embodiment of Formula I, a compound of Formula Id has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 1 and 4′ positions, the 3 and 2′ positions, or the 4 and 1′positions.

In another embodiment of Formula Id, the R groups are bound with pointsof attachment at the 1 and 4′ positions.

In another embodiment of Formula Id, the R groups are bound with pointsof attachment at the 3 and 2′ positions.

In another embodiment of Formula Id, the R groups are bound with pointsof attachment at the 4 and 1′ positions.

In another embodiment of Formula Id, both R groups are hydrogen.

In another embodiment of Formula Id, both R groups are halogen.

In another embodiment of Formula Id, both R groups are fluorine.

In another embodiment of Formula Id, both R groups are chlorine.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Id, both R groups are methyl.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula Id, both R groups are methoxy.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula Id, both R groups aremethylcarbonyloxy.

In another embodiment of Formula Id, both values of z are 1.

In another embodiment of Formula Id, both values of z are 2.

In another embodiment of Formula Id, both values of z are 3.

In another embodiment of Formula Id, both values of z are 4.

In another embodiment of Formula Id, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Id, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Id, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Id, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula Id, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula Id, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula Id, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula Id, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula Id, both R groups are methylcarbonyloxyand both values of z are 1.

In another embodiment of Formula Id, both R groups are methylcarbonyloxyand both values of z are 2.

In another embodiment of Formula Id, both R groups are methylcarbonyloxyand both values of z are 3.

In another embodiment of Formula Id, both R groups are methylcarbonyloxyand both values of z are 4.

In another embodiment, a compound of the invention has the structure ofFormula II:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4;

-   -   wherein the —(CH₂)_(z)C(═O)OH moiety and the        —(CH₂)_(z)C(═O)O-naltrexone moiety are bound with points of        attachment selected from the 1 and 1′ positions, the 1 and 4′        positions, the 2 and 2′ positions, or the 2 and 3′ positions;        and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 1 and 1′ positions, then the R groups are boundat the 2 and 2′ positions, the 3 and 3′ positions, or the 4 and 4′positions;

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 1 and 4′ positions, then the R groups are boundat the 2 and 3′ positions, the 3 and 2′ positions, or the 4 and 1′positions;

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 2 and 2′ positions, then the R groups are boundat the 1 and 1′ positions, the 3 and 3′ positions, or the 4 and 4′positions; or

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 2 and 3′ positions, then the R groups are boundat the 1 and 4′ positions, the 3 and 2′ positions, or the 4 and 1′positions.

In another embodiment of Formula II, both R groups are hydrogen.

In another embodiment of Formula II, both R groups are halogen.

In another embodiment of Formula II, both R groups are fluorine.

In another embodiment of Formula II, both R groups are chlorine.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula II, both R groups are methyl.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula II, both R groups are methoxy.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula II, both R groups aremethylcarbonyloxy.

In another embodiment of Formula II, both values of z are 1.

In another embodiment of Formula II, both values of z are 2.

In another embodiment of Formula II, both values of z are 3.

In another embodiment of Formula II, both values of z are 4.

In another embodiment of Formula II, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula II, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula II, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula II, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula II, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula II, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula II, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula II, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula II, both R groups are methylcarbonyloxyand both values of z are 1.

In another embodiment of Formula II, both R groups are methylcarbonyloxyand both values of z are 2.

In another embodiment of Formula II, both R groups are methylcarbonyloxyand both values of z are 3.

In another embodiment of Formula II, both R groups are methylcarbonyloxyand both values of z are 4.

In another embodiment of Formula II, a compound of Formula IIa has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 2 and 2′ positions, the 3 and 3′ positions, or the 4 and 4′positions.

In another embodiment of Formula IIa, the R groups are bound with pointsof attachment at the 2 and 2′ positions.

In another embodiment of Formula IIa, the R groups are bound with pointsof attachment at the 3 and 3′ positions.

In another embodiment of Formula IIa, the R groups are bound with pointsof attachment at the 4 and 4′ positions.

In another embodiment of Formula IIa, both R groups are hydrogen.

In another embodiment of Formula IIa, both R groups are halogen.

In another embodiment of Formula IIa, both R groups are fluorine.

In another embodiment of Formula IIa, both R groups are chlorine.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IIa, both R groups are methyl.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula IIa, both R groups are methoxy.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula IIa, both R groups aremethylcarbonyloxy.

In another embodiment of Formula IIa, both values of z are 1.

In another embodiment of Formula IIa, both values of z are 2.

In another embodiment of Formula IIa, both values of z are 3.

In another embodiment of Formula IIa, both values of z are 4.

In another embodiment of Formula IIa, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IIa, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IIa, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIa, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula IIa, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula IIa, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula IIa, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula IIa, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula IIa, both R groups aremethylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIa, both R groups aremethylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIa, both R groups aremethylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IIa, both R groups aremethylcarbonyloxy and both values of z are 4.

In another embodiment of Formula II, a compound of Formula IIb has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 1 and 1′ positions, the 3 and 3′ positions, or the 4 and 4′positions.

In another embodiment of Formula IIb, the R groups are bound with pointsof attachment at the 1 and 1′ positions.

In another embodiment of Formula IIb, the R groups are bound with pointsof attachment at the 3 and 3′ positions.

In another embodiment of Formula IIb, the R groups are bound with pointsof attachment at the 4 and 4′ positions.

In another embodiment of Formula IIb, both R groups are hydrogen.

In another embodiment of Formula IIb, both R groups are halogen.

In another embodiment of Formula IIb, both R groups are fluorine.

In another embodiment of Formula IIb, both R groups are chlorine.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IIb, both R groups are methyl.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula IIb, both R groups are methoxy.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula IIb, both R groups aremethylcarbonyloxy.

In another embodiment of Formula IIb, both values of z are 1.

In another embodiment of Formula IIb, both values of z are 2.

In another embodiment of Formula IIb, both values of z are 3.

In another embodiment of Formula IIb, both values of z are 4.

In another embodiment of Formula IIb, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IIb, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IIb, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIb, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula IIb, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula IIb, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula IIb, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula IIb, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula IIb, both R groups aremethylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIb, both R groups aremethylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIb, both R groups aremethylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IIb, both R groups aremethylcarbonyloxy and both values of z are 4.

In another embodiment of Formula II, a compound of Formula IIc has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 2 and 3′ positions, the 3 and 2′ positions, or the 4 and 1′positions.

In another embodiment of Formula IIc, the R groups are bound with pointsof attachment at the 2 and 3′ positions.

In another embodiment of Formula IIc, the R groups are bound with pointsof attachment at the 3 and 2′ positions.

In another embodiment of Formula IIc, the R groups are bound with pointsof attachment at the 4 and 1′ positions.

In another embodiment of Formula IIc, both R groups are hydrogen.

In another embodiment of Formula IIc, both R groups are halogen.

In another embodiment of Formula IIc, both R groups are fluorine.

In another embodiment of Formula IIc, both R groups are chlorine.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl. In another embodiment of Formula IIc, both R groups aremethyl.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula IIc, both R groups are methoxy.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula IIc, both R groups aremethylcarbonyloxy.

In another embodiment of Formula IIc, both values of z are 1.

In another embodiment of Formula IIc, both values of z are 2.

In another embodiment of Formula IIc, both values of z are 3.

In another embodiment of Formula IIc, both values of z are 4.

In another embodiment of Formula IIc, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IIc, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IIc, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIc, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula IIc, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula IIc, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula IIc, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula IIc, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula IIc, both R groups aremethylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IIc, both R groups aremethylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IIc, both R groups aremethylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IIc, both R groups aremethylcarbonyloxy and both values of z are 4.

In another embodiment of Formula II, a compound of Formula IId has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, orunsubstituted C₁-C₄ alkylcarbonyloxy;

both values of z, always being the same, are 1, 2, 3, or 4; and

wherein the R groups are bound with points of attachment selected fromthe 1 and 4′ positions, the 3 and 2′ positions, or the 4 and 1′positions.

In another embodiment of Formula IId, the R groups are bound with pointsof attachment at the 1 and 4′ positions.

In another embodiment of Formula IId, the R groups are bound with pointsof attachment at the 3 and 2′ positions.

In another embodiment of Formula IId, the R groups are bound with pointsof attachment at the 4 and 1′ positions.

In another embodiment of Formula IId, both R groups are hydrogen.

In another embodiment of Formula IId, both R groups are halogen.

In another embodiment of Formula IId, both R groups are fluorine.

In another embodiment of Formula IId, both R groups are chlorine.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IId, both R groups are methyl.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkoxy.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkoxy.

In another embodiment of Formula IId, both R groups are methoxy.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy.

In another embodiment of Formula IId, both R groups aremethylcarbonyloxy.

In another embodiment of Formula IId, both values of z are 1.

In another embodiment of Formula IId, both values of z are 2.

In another embodiment of Formula IId, both values of z are 3.

In another embodiment of Formula IId, both values of z are 4.

In another embodiment of Formula IId, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IId, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IId, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IId, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkoxy and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 3.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkoxy and both values of z are 4.

In another embodiment of Formula IId, both R groups are methoxy and bothvalues of z are 1.

In another embodiment of Formula IId, both R groups are methoxy and bothvalues of z are 2.

In another embodiment of Formula IId, both R groups are methoxy and bothvalues of z are 3.

In another embodiment of Formula IId, both R groups are methoxy and bothvalues of z are 4.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkcarbonyloxy and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkylcarbonyloxy and both values of z are 4.

In another embodiment of Formula IId, both R groups aremethylcarbonyloxy and both values of z are 1.

In another embodiment of Formula IId, both R groups aremethylcarbonyloxy and both values of z are 2.

In another embodiment of Formula IId, both R groups aremethylcarbonyloxy and both values of z are 3.

In another embodiment of Formula IId, both R groups aremethylcarbonyloxy and both values of z are 4.

The compounds of Formula I are dimeric compounds, each containing twomolecules of naltrexone covalently bound to a pro-moiety. Accordingly,in another embodiment, a compound of Formula I, for example a compoundof Formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable saltthereof, is administered to a subject and metabolized in vivo to releasenaltrexone and an intermediate depicted as a compound of Formula II. Theresultant compound of Formula II, for example a compound of Formula IIa,IIb, IIc or IId, or a pharmaceutically acceptable salt thereof, may alsobe metabolized in vivo to release naltrexone. In another embodiment, acompound of Formula II, for example a compound of Formula IIa, IIb, IIcor IId, or a pharmaceutically acceptable salt thereof, is administeredto a subject and metabolized in vivo to release naltrexone.

Certain embodiments of compounds of Formula I or II are shown below inTables A and B, respectively. Compounds of Formulas I or II, orpharmaceutically acceptable salts thereof, and compounds of Tables A andB, are sometimes referred to herein as “compounds of the invention,” or“compounds provided herein.”

TABLE A Compound Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE B Compound Structure  1i

 2i

 3i

 4i

 5i

 6i

 7i

 8i

 9i

10i

11i

12i

13i

14i

15i

16i

17i

18i

19i

20i

21i

22i

23i

24i

25i

26i

Also provided herein are pharmaceutical compositions comprising acompound of Formula I or II, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. In one embodiment,the composition is administered to a subject in need of the treatment ofopioid dependence. In another embodiment, the composition isadministered to a subject in need of the treatment of alcoholdependence. In another embodiment, the composition is administered to asubject in need of the treatment of alcohol use disorder. In anotherembodiment, the composition is administered to a subject in need of theprevention of opioid dependence. In another embodiment, the compositionis administered to a subject in need of the prevention of relapse toopioid dependence. In another embodiment, the composition isadministered to a subject in need of the prevention of alcoholdependence.

In any of the compositions or methods as described herein, the compoundof Formula I or II, or a pharmaceutically acceptable salt thereof, ispresent and/or administered in a therapeutically effective amount.

In any of the compositions or methods as described herein, the compoundof Formula Ia, Ib, Ic, Id, IIa, IIb, IIc or IId, or a pharmaceuticallyacceptable salt thereof, is present and/or administered in atherapeutically effective amount.

In another embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is converted to one equivalent of naltrexoneand one equivalent of a compound of Formula II, upon parenteraladministration. In another embodiment, a compound of Formula I, or apharmaceutically acceptable salt thereof, is converted to up to oneequivalent of naltrexone and up to one equivalent of a compound ofFormula II, upon parenteral administration. In another embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof, isconverted to from about 0.6 to 0.95 equivalents of naltrexone and acompound of Formula II, upon parenteral administration. In anotherembodiment, a compound of Formula I, or a pharmaceutically acceptablesalt thereof, is converted to from about 0.7 to 0.95 equivalents ofnaltrexone and a compound of Formula II, upon parenteral administration.In another embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is converted to from about 0.8 to 0.95equivalents of naltrexone and a compound of Formula II, upon parenteraladministration. For example, about 0.7 equivalents, about 0.75equivalents, about 0.8 equivalents, about 0.85 equivalents, about 0.9equivalents, about 0.95 equivalents, or greater than 0.95 equivalents ofthe total dose of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, administered is converted to naltrexone and acompound of Formula II upon parenteral administration. In anotherembodiment, a compound of Formula I, or a pharmaceutically acceptablesalt thereof, is essentially completely converted to naltrexone and acompound of Formula II, upon parenteral administration. In anotherembodiment, the parenteral administration is via the intramuscularroute.

In another embodiment, the resultant compound of Formula II is convertedin vivo to one equivalent of naltrexone. In another embodiment, theresultant compound of Formula II is converted in vivo to up to oneequivalent of naltrexone. For example, about 0.5 equivalents, about 0.6equivalents, about 0.7 equivalents, about 0.75 equivalents, about 0.8equivalents, about 0.85 equivalents, about 0.9 equivalents, about 0.95equivalents, or greater than 0.95 equivalents of the total amount of acompound of Formula II is converted to naltrexone. In anotherembodiment, the compound of Formula II is essentially completelyconverted to naltrexone.

In another embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, may be converted in vivo to two equivalents ofnaltrexone, upon parenteral administration. In another embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof,may be converted to up to two equivalents of naltrexone, upon parenteraladministration. For example, about 1.2 equivalents, about 1.3equivalents, about 1.4 equivalents, about 1.5 equivalents, about 1.6equivalents, about 1.7 equivalents, about 1.8 equivalents, or greaterthan 1.8 equivalents of the total dose of a compound of Formula I, or apharmaceutically acceptable salt thereof, administered is converted tonaltrexone, upon parenteral administration. In another embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof, isessentially completely converted to naltrexone, upon parenteraladministration. In another embodiment, the parenteral administration isvia the intramuscular route.

In another embodiment, any one of the compounds 1 to 26 (see Table A),or a pharmaceutically acceptable salt thereof, may be converted in vivoto two equivalents of naltrexone, upon parenteral administration. Inanother embodiment, any one of the compounds 1 to 26, or apharmaceutically acceptable salt thereof, may be converted in vivo to upto two equivalents of naltrexone, upon parenteral administration. Forexample, about 1.2 equivalents, about 1.3 equivalents, about 1.4equivalents, about 1.5 equivalents, about 1.6 equivalents, about 1.7equivalents, about 1.8 equivalents, or greater than 1.8 equivalents ofthe total dose of any one of the compounds 1 to 26, or apharmaceutically acceptable salt thereof, administered is converted tonaltrexone, upon parenteral administration. In another embodiment, anyone of the compounds 1 to 26, or a pharmaceutically acceptable saltthereof, is essentially completely converted to naltrexone, uponparenteral administration. In another embodiment, the parenteraladministration is via the intramuscular route.

In another embodiment, any one of the compounds 1i to 26i (see Table B)may be converted in vivo to one equivalent of naltrexone. In anotherembodiment, any one of the compounds 1i to 26i may be converted in vivoto up to one equivalent of naltrexone. For example, about 0.7equivalents, about 0.75 equivalents, about 0.8 equivalents, about 0.85equivalents, about 0.9 equivalents, about 0.95 equivalents, or greaterthan 0.95 equivalents of the total amount of any one of the compounds 1ito 26i is converted to naltrexone. In another embodiment, any one of thecompounds 1i to 26i is essentially completely converted to naltrexone.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeledcompounds are useful in drug or substrate tissue distribution studies.In another embodiment, substitution with heavier isotopes such asdeuterium affords greater metabolic stability (for example, increased invivo half-life or reduced dosage requirements). In another embodiment,the compounds described herein include a ²H (i.e., deuterium) isotope.Isotopically-labeled compounds are prepared by any suitable method or byprocesses using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent otherwise employed.

Methods of Treatment

The compounds of the invention can be used in a method of treating adisease or condition in a subject wherein treatment with a compound ofthe invention would be beneficial, said method comprising administeringto the subject a compound of the invention, or a pharmaceuticalcomposition comprising a compound of the invention.

The compounds of the invention can be used to treat a disease orcondition selected from the group consisting of opioid dependence oralcohol dependence in a subject in need thereof.

The compounds of the invention can be used to prevent a disease orcondition selected from the group consisting of opioid dependence,relapse to opioid dependence, or alcohol dependence in a subject in needthereof.

In one embodiment, the compounds of the invention can be used to treatopioid dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used totreat alcohol dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used totreat alcohol use disorder in a subject in need thereof.

In yet another embodiment, the compounds of the invention can be used toprevent opioid dependence in a subject in need thereof.

In yet another embodiment, the compounds of the invention can be used toprevent relapse to opioid dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used toprevent alcohol dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used totreat addiction in a subject in need thereof. The addiction can be drugaddiction or alcohol addiction.

The drug addiction can be one or more of opioid addiction (i.e., opioiddependence) or stimulant addiction. The opioid can be one or more offentanyl, morphine, oxymorphone, buprenorphine, hydromorphone,oxycodone, hydrocodone, or the like. The drug addiction can also be oneor more of diamorphine (i.e., heroin), cocaine, nicotine, andamphetamine.

In one embodiment, compounds of the invention can be used to treat adisease or condition in a subject, wherein the subject has a toleranceto opioid medication, the subject has a history of opioid dependency orabuse, the subject is at risk of opioid dependency or abuse, or incircumstances wherein it is desirable that the risk of opioid dependenceor opioid addiction in the subject is minimized.

The compounds of the invention can also be used to treat alcoholaddiction, which can also be referred to as alcoholism. “Alcoholism”refers to an addictive disease or disorder characterized by an inabilityto control the intake of alcohol, i.e., a continued excessive orcompulsive use of alcoholic drinks. Alcoholism may involve changes anindividual's ability to metabolize alcohol as well. Diagnosis ofalcoholism can be made by psychiatric examination.

In one aspect, the compounds provided herein are useful in treatment orprevention of opioid dependence or alcohol dependence by being convertedin vivo into naltrexone, which acts as an antagonist of the μ-opioidreceptor.

In one embodiment of the methods described herein, the subject is human.

Administration/Dosage/Formulations

The compounds of the invention enable compositions with desirableproperties and advantages. For example, the compositions can beadministered once per month, or once per two months, or once per threemonths, which is particularly desirable for the subjects describedherein. Such compositions can provide many therapeutic benefits that arenot achieved with corresponding shorter acting, or immediate-releaseoral preparations of naltrexone. For example, the composition canmaintain lower, more steady plasma concentrations of naltrexone.

In one embodiment, the compound of the invention is administered in acomposition suitable for parenteral administration. In anotherembodiment, the parenteral administration is by injection. In anotherembodiment, the parenteral administration is by intramuscular injection.Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. OMEGAVEN® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In one embodiment, a pharmaceutical composition in accordance with theinvention may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. In anotherembodiment, the material is crystalline.

In another embodiment, a pharmaceutical composition may be accomplishedby dissolving or suspending the compound of the invention in an oilvehicle.

In another embodiment, a pharmaceutical composition may be accomplishedby forming microencapsule matrices of the compound of the invention inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Injectable compositions are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

In another aspect, provided herein is a pharmaceutical compositioncomprising at least one compound of the invention, together with apharmaceutically acceptable carrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the rate of metabolism of the particular compoundemployed, the rate of clearance of the compound, the duration of thetreatment, other drugs, compounds or materials used in combination withthe compound, the age, sex, weight, condition, general health and priormedical history of the patient being treated, and like factors wellknown in the medical arts.

A medical doctor, e.g., physician, having ordinary skill in the art mayreadily determine and prescribe the effective amount of thepharmaceutical composition required. For example, the physician couldbegin administration of the pharmaceutical composition to dose acompound of the invention at levels lower than that required in order toachieve the desired therapeutic effect and gradually increase the dosageuntil the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subjects tobe treated; each unit containing a predetermined quantity of thecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the compound and the particular therapeuticeffect to be achieved, and (b) the limitations inherent in the art ofcompounding/formulating such a compound for the treatment or preventionof opioid dependence or alcohol dependence in a subject.

In one embodiment, the compounds of the invention are formulated usingone or more pharmaceutically acceptable carriers. In one embodiment, thepharmaceutical compositions of the invention comprise a therapeuticallyeffective amount of a compound of the invention and a pharmaceuticallyacceptable carrier.

In some embodiments, a single dose of a compound of Formula I or II, ora pharmaceutically acceptable salt thereof, is from about 1 mg to about5,000 mg. In some embodiments, a single dose of a compound used incompositions described herein is less than about 2,000 mg, or less thanabout 1,800 mg, or less than about 1,600 mg, or less than about 1,400mg, or less than about 1,300 mg, or less than about 1,200 mg, or lessthan about 1,100 mg, or less than about 1,000 mg, or less than about 900mg, or less than about 800 mg, or less than about 750 mg, or less thanabout 700 mg, or less than about 600 mg, or less than about 500 mg, orless than about 300 mg or less than about 100 mg. For example, a singledose is about 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, 1,200 mg, 1,250 mg,1,300 mg, 1,350 mg, 1,400 mg, 1,450 mg, 1,500 mg, 1,550 mg, 1,600 mg,1,650 mg, 1,700 mg, 1,750 mg, 1,800 mg, 1,850 mg, 1,900 mg 1,950 mg, orabout 2,000 mg of a compound of Formula I. In a particular embodiment,the dose is administered as a single parenteral injection. In a specificembodiment, the dose is administered as a single intramuscularinjection.

For comparison purposes, VIVITROL® (naltrexone for extended-releaseinjectable suspension) is administered intramuscularly every four weeksor once a month at a dose of 380 mg naltrexone. REVIA® (naltrexonehydrochloride tablets USP) can be administered orally once per day at adose of 50 mg naltrexone hydrochloride.

In some embodiments, a single intramuscular injection is administeredwith a dose of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, of from about 500 mg to about 2,200 mg. In someembodiments, a single intramuscular injection is administered with adose of a compound of Formula I, or a pharmaceutically acceptable saltthereof, of from about 750 mg to about 2,000 mg. In some embodiments, asingle intramuscular injection is administered with a dose of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, of fromabout 1,000 mg to about 2,000 mg. In some embodiments, a singleintramuscular injection is administered with a dose of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, of from about1,200 mg to about 1,800 mg.

In another embodiment, a pharmaceutical composition comprises a compoundof Formula I or II or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; wherein the composition provides aduration of release of naltrexone of, from about 1 week to about 15weeks, following parenteral administration. In another embodiment, theduration of release of naltrexone is from about 2 weeks to about 15weeks, or from about 4 weeks to about 15 weeks, or from about 6 weeks toabout 15 weeks, or from about 8 weeks to about 15 weeks, or from about 8weeks to about 14 weeks, or from about 8 weeks to about 12 weeks. Inanother embodiment, the duration of release of naltrexone is about 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks. Inanother embodiment, the duration of release of naltrexone is about 8weeks. In another embodiment, the duration of release of naltrexone isabout 9 weeks. In another embodiment, the duration of release ofnaltrexone is about 10 weeks. In another embodiment, the duration ofrelease of naltrexone is about 11 weeks. In another embodiment, theduration of release of naltrexone is about 12 weeks. In anotherembodiment, the duration of release of naltrexone is about 13 weeks. Inanother embodiment, the duration of release of naltrexone is about 14weeks. In another embodiment, the duration of release of naltrexone isabout 15 weeks. In another embodiment, the duration of release ofnaltrexone is about 1 month. In another embodiment, the duration ofrelease of naltrexone is about 2 months. In another embodiment, theduration of release of naltrexone is about 3 months. In anotherembodiment, the parenteral administration is intramuscularadministration.

In another embodiment, a pharmaceutical composition comprises a compoundof Formula I or II or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; wherein the composition provides aminimum naltrexone blood plasma concentration of, from about 0.5 toabout 10 ng/mL, following parenteral administration. In anotherembodiment, the minimum naltrexone blood plasma concentration is atleast from about 0.7 to about 10 ng/mL, or from about 0.8 to about 8.0ng/mL, or from about 1.0 to about 8.0 ng/mL, or from about 1.0 to about6.0 ng/mL, or from about 1.5 to about 6.0 ng/mL, or from about 1.5 toabout 4.0 ng/mL, or from about 1.5 to about 3.0 ng/mL, or from about 1.5to about 2.5 ng/mL, or from about 1.5 to about 2.0 ng/mL, or from about2.0 to about 2.5 ng/mL. In another embodiment, the minimum naltrexoneblood plasma concentration is about 0.5 ng/mL, 0.8 ng/mL, 1.0 ng/mL, 1.1ng/mL, 1.2 ng/mL, 1.3 ng/mL, 1.4 ng/mL, 1.5 ng/mL, 1.6 ng/mL, 1.7 ng/mL,1.8 ng/mL, 1.9 ng/mL, 2.0 ng/mL, 2.1 ng/mL, 2.2 ng/mL, 2.3 ng/mL. 2.4ng/mL, or 2.5 ng/mL. In another embodiment, the minimum naltrexone bloodplasma concentration is about 1.0 ng/mL. In another embodiment, theminimum naltrexone blood plasma concentration is about 1.5 ng/mL. Inanother embodiment, the minimum naltrexone blood plasma concentration isabout 2.0 ng/mL. In another embodiment, the minimum naltrexone bloodplasma concentration is about 2.5 ng/mL. In another embodiment, theminimum naltrexone blood plasma concentration is about 3.0 ng/mL. Inanother embodiment, the parenteral administration is intramuscularadministration.

In other embodiments, a pharmaceutical composition comprises a compoundof Formula I or II or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; wherein the composition provides aminimum naltrexone blood plasma concentration of, from about 0.5 toabout 3.0 ng/mL, following parenteral administration, for a duration of,from about 1 week to about 15 weeks. In another embodiment, the minimumnaltrexone blood plasma concentration is at least from about 0.7 toabout 3.0 ng/mL, or from about 0.8 to about 2.5 ng/mL, or from about 1.0to about 2.5 ng/mL, or from about 1.0 to about 2.0 ng/mL, or from about1.0 to about 1.5 ng/mL, or from about 1.5 to about 2.5 ng/mL, or fromabout 1.5 to about 2.0 ng/mL, for a duration of, from about 1 week toabout 15 weeks, or from about 2 weeks to about 14 weeks, or from about 4weeks to about 14 weeks, or from about 6 weeks to about 14 weeks, orfrom about 8 weeks to about 12 weeks, or from about 10 weeks to about 12weeks. In another embodiment, the minimum naltrexone blood plasmaconcentration is about 1.0 ng/mL, 1.1 ng/mL, 1.2 ng/mL, 1.3 ng/mL, 1.4ng/mL, 1.5 ng/mL, 1.6 ng/mL, 1.7 ng/mL, 1.8 ng/mL, 1.9 ng/mL, 2.0 ng/mL,2.1 ng/mL, 2.2 ng/mL, 2.3 ng/mL. 2.4 ng/mL, or 2.5 ng/mL, for a durationof about 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks,or about 14 weeks. In another embodiment, the minimum naltrexone bloodplasma concentration is about 1.0 ng/mL for a duration of about 14weeks. In another embodiment, the minimum naltrexone blood plasmaconcentration is about 1.5 ng/mL for a duration of about 14 weeks. Inanother embodiment, the minimum naltrexone blood plasma concentration isabout 2.0 ng/mL for a duration of about 14 weeks. In another embodiment,the minimum naltrexone blood plasma concentration is about 2.0 ng/mL fora duration of about 12 weeks. In another embodiment, the minimumnaltrexone blood plasma concentration is about 2.0 ng/mL for a durationof about 10 weeks. In another embodiment, the minimum naltrexone bloodplasma concentration is about 3.0 ng/mL for a duration of about 10weeks. In another embodiment, the minimum naltrexone blood plasmaconcentration is about 3.0 ng/mL for a duration of about 8 weeks. Inanother embodiment, the parenteral administration is intramuscularadministration.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 26 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.0 ng/mL,following parenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 26 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.5 ng/mL,following parenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 26 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 2.0 ng/mL,following parenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 26 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.0 ng/mL,following parenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 26 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.5 ng/mL,following parenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 26 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 2.0 ng/mL,following parenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 2or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.0 ng/mL, followingparenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 2or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.5 ng/mL, followingparenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 2or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 2.0 ng/mL, followingparenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 2or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.0 ng/mL, followingparenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 2or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.5 ng/mL, followingparenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 2or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 2.0 ng/mL, followingparenteral administration, for a duration of about 12 weeks.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,inhalation spray, sublingual or topical. The compounds for use in theinvention may be formulated for administration by any suitable route,such as for oral or parenteral, for example, transdermal, transmucosal(e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal(e.g., trans- and perivaginally), (intra)nasal and (trans)rectal,intravesical, intrapulmonary, intraduodenal, intragastrical,intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial,intravenous, intrabronchial, inhalation, and topical administration. Theterm parenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques. In one embodiment, the parenteraladministration is by injection. In another embodiment, the parenteraladministration is by intramuscular injection.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizing ordispersing agents may be used, such as a polysorbate (e.g., polysorbate20). Other formulatory agents may include preservatives and buffers asare known in the art, such as a phosphate buffer.

It is contemplated that any one of the compounds of the invention can bepresent as a co-crystal, solvate, hydrate, polymorph, or the like.Further, the compounds of the invention have a defined stereochemistryand one skilled in the art can also envision other enantiomers,diastereoisomers, or racemates of the compounds of the invention.

The present invention provides methods for the synthesis of thecompounds of each of the formulae described herein. Compounds of thepresent invention can be prepared in a variety of ways usingcommercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. The following descriptions of synthetic methodsare designed to illustrate, but not to limit, general procedures for thepreparation of compounds of the present invention.

General methods for the preparation of compounds as described herein aremodified by the use of appropriate reagents and conditions, for theintroduction of the various moieties found in the Formulae as providedherein. Compounds described herein are synthesized using any suitableprocedures starting from compounds that are available from commercialsources, or are prepared using procedures described herein.

The processes generally provide the desired final compound at or nearthe end of the overall process, although it may be desirable in certaininstances to further convert the compound to a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate or co-crystal thereof.

In the synthetic scheme and examples provided herein, the followingabbreviations may be used:

DMF=dimethylformamide

DMAP=4-(dimethylamino)pyridine

DIPEA (DIEA)=N,N-diisopropylethylamine

Pd(dba)₂=bis(dibenzylideneacetone)palladium(0)

Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0)

PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate

TBS=tert-butyldimethylsilyl

THF=tetrahydrofuran

TFA=trifluoroacetic acid

TEA=triethylamine

TMSOK=potassium trimethylsilanolate

TBME (MTBE)=tert-butyl methyl ether

T₃P=propylphosphonic anhydride

XPhos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

In one embodiment, a general method for synthesizing one or morecompounds of Formula I is provided below (Scheme 1).

As depicted for Compound 2 in Scheme 1 above, the synthesis of one ormore compounds of Formula I can be carried out using various syntheticpathways. The common intermediate in every route is2,2′-(naphthalene-2,6-diyl)diacetic acid.2,2′-(naphthalene-2,6-diyl)diacetic acid can be accessed in several waysincluding, but not limited to, the following:

-   -   (a) a homologation route starting from        naphthalene-2,6-diyldimethanol, followed by activation,        cyanation, and hydrolysis;    -   (b) Pd-mediated cross-coupling using di-tert-butyl malonate and        2,6-dibromonaphthalene, followed by ester hydrolysis and        decarboxylation; or    -   (c) Pd-mediated cross-coupling using        tert-butyl((1-methoxyvinyl)oxy)dimethylsilane and        2,6-halonaphthalene, followed by ester hydrolysis.        The synthesized 2,2′-(naphthalene-2,6-diyl)diacetic acid can,        for example, (a) be coupled to 2 equivalents of naltrexone using        standard coupling reagents (such as        (benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate (PyBOP), propylphosphonic anhydride (T₃P),        or the like), or (b) first converted to        2,2′-(naphthalene-2,6-diyl)diacetyl chloride using Ghosez's        reagent (1-chloro-N,N,2-trimethyl-1-propenylamine) or SOCl₂        (thionyl chloride), followed by naltrexone addition.

EXAMPLES

The invention is further illustrated by the following examples, whichshould not be construed as further limiting.

Examples Example 1: Synthesis of Compounds of the Invention 1.1 Compound1 Synthesis of 1,5-bis(bromomethyl)naphthalene

1,5-Dimethylnaphthalene (1.0 g, 6.4 mmol), N-bromosuccinimide (2.3 g,12.8 mmol), benzyl peroxide (31 mg, 0.13 mmol) were dissolved indichloroethane (10 mL). The reaction was heated to reflux and left tostir overnight for 18 hours. The reaction was cooled to room temperatureand a solid crashed out of solution, which was filtered and washed withcold ethyl acetate. The solid was re-dissolved in dichloromethane (30mL) and washed with saturated sodium hydrogen carbonate solution (3×30mL) and brine (3×30 mL). The organic phase was dried with sodiumsulphate, filtered and reduced to dryness under vacuum. The crude solidwas then triturated with hot ethyl acetate (10 mL) and filtered. Thisyielded 1,5-bis(bromomethyl)naphthalene as a white powder (1.22 g, 60%).

¹H NMR (396 MHz, CDCl₃): δ 8.18 (d, 2H), 7.60 (d, 2H), 7.55 (t, 2H),4.96 (s, 4H).

Synthesis of 2,2′-(naphthalene-1,5-diyl)diacetonitrile

1,5-Bis(bromomethyl)naphthalene (1.2 g, 3.82 mmol), potassium cyanide(746 mg, 11 mmol) and tetrabutylammonium bromide (615 mg, 1.91 mmol)were dissolved in dichloromethane:water (15 mL: 15 mL) and stirred atroom temperature for 18 hours. The reaction was quenched with 2 M sodiumhydroxide and stirred for 15 minutes. The aqueous phase was extractedwith dichloromethane (3×50 mL); the organic phases were combined, driedusing sodium sulphate and reduced to dryness under vacuum. The crudeproduct was then filtered through a plug of silica to remove impuritiesto yield 2,2′-(naphthalene-1,5-diyl)diacetonitrile as a yellow solid(649 mg, 82%).

¹H NMR (396 MHz, CDCl₃): δ 7.92 (d, 2H), 7.69 (d, 2H), 7.61 (d, 2H),4.18 (s, 4H).

Synthesis of 2,2′-(naphthalene-1,5-diyl)diacetic Acid

2,2′-(Naphthalene-1,5-diyl)diacetonitrile (649 mg, 3.15 mmol) wasdissolved in sulphuric acid:acetic acid:water (4 mL:4 mL:4 mL) andheated to reflux for 4 hours. The reaction was allowed to cool back downto room temperature and the reaction mixture was diluted with water (30mL). The aqueous was extracted with 2-methyl tetrahydrofuran, dried withsodium sulphate and reduced to dryness under vacuum. The crude solidobtained was triturated with diethyl ether to yield2,2′-(naphthalene-1,5-diyl)diacetic acid as a grey solid (636 mg, 83%).

¹H NMR (396 MHz, DMSO-d₆): δ 12.39 (s, 2H), 7.90 (d, 2H), 7.49 (t, 2H),7.43 (d, 2H), 4.04 (s, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-1,5-diyl)diacetate

To a solution of 2,2′-(naphthalene-1,5-diyl)diacetic acid (1.0 g, 4.09mmol) in tetrahydrofuran (20 mL) was added triethylamine (1.71 mL, 12.28mmol), naltrexone (2.80 g, 8.29 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(4.70 g, 9.01 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction was therefore quenched with water(70 mL) and extracted with dichloromethane (3×75 mL). The organic phaseswere combined and washed with saturated sodium bicarbonate solution(3×100 mL), dried using a phase separator and reduced to dryness undervacuum. The crude foam was purified in two batches via reverse phasechromatography (pH 9 ammonium bicarbonate buffer, 30% to 100%acetonitrile). This yieldedbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-1,5-diyl)diacetate as a colourless solid afterextraction with ethyl acetate from the relevant fractions (1.6 g, 44%).

¹H NMR (396 MHz, DMSO-d₆): δ 7.90-8.10 (m, 2H), 7.47-7.70 (m, 4H), 6.87(d, 2H), 6.64 (d, 2H), 5.09 (s, 2H), 4.90 (s, 2H), 4.41 (s, 4H),3.08-3.20 (m, 2H), 2.96-3.08 (m, 2H), 2.75-2.96 (m, 2H), 2.48-2.69 (m,2H), 2.19-2.41 (m, 5H), 1.99-2.16 (m, 2H), 1.82-1.93 (m, 2H), 1.61-1.82(m, 2H), 1.32-1.55 (m, 2H), 1.18-1.28 (m, 2H), 0.69-1.01 (m, 2H), 0.43(d, 4H), 0.11 (d, 4H). [M+H]⁺ 891.40.

1.2 Compound 2 Synthesis of 2,2′-(naphthalene-2,6-diyl)diacetonitrile

To a solution of 1,6-di(hydroxymethyl)naphthylene (3.5 g, 18.6 mmol) indimethylformamide (70 mL) at 5° C. was added triethylamine (6.5 mL, 46.5mmol), followed by methanesulfonyl chloride (3.31 mL, 42.8 mmol) over 2min. The reaction mixture was stirred for 3 hours and then potassiumcyanide (3.6 g, 55.8 mmol) was added. The reaction mixture was heated at50° C. for 4 hours, cooled to room temperature, diluted with ethylacetate (100 mL) and washed with diluted brine (4×150 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was dissolved in dimethylformamide (50 mL)and potassium cyanide (3.6 g, 55.8 mmol) added and the reaction mixtureheated at 90° C. for 3 hours. The reaction was cooled, poured into water(500 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (3×300 mL), dried over magnesiumsulfate, filtered and concentrated under reduced pressure to give2,2′-(naphthalene-2,6-diyl)diacetonitrile (2.95 g, 89% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.85-7.80 (m, 4H), 7.42 (dd, 2H), 3.92 (s,4H).

Synthesis of 2,2′-(naphthalene-2,6-diyl)diacetic Acid

To a mixture of 2,2′-(naphthalene-2,6-diyl)diacetonitrile (2.95 g, 14.3mmol), water (13 mL) and acetic acid (18 mL) was added sulphuric acid(13 mL). The reaction mixture was heated at reflux for 20 hours, cooledand then poured into water (350 mL) at 5° C. The resulting precipitatewas filtered, washed with water and dried under suction for 30 min. Thea half of the resulting solid was added to ethyl acetate (50 mL) and thesuspension sonicated for 30 min. The resulting solid was collected byfiltration and dried to give 2,2′-(naphthalene-2,6-diyl)diacetic acid(0.88 g, 25% yield).

¹H NMR (300 MHz, 1,4-dioxane-d₈): δ 7.74 (d, 2H), 7.70 (s, 2H), 7.40 (d,2H), 3.71 (s, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-2,6-diyl)diacetate

To a solution of 2,2′-(naphthalene-2,6-diyl)diacetic acid (0.25 g, 1.02mmol) in tetrahydrofuran (30 mL) was added Ghosez's reagent (328 mg,2.46 mmol). The reaction mixture as stirred for 90 min and then amixture of naltrexone (804 mg, 2.35 mmol) and triethylamine (0.43 mL,3.07 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture wasstirred a further hour and then diluted with ethyl acetate (50 mL) andwashed with diluted aqueous solution of sodium hydrogencarbonate (50mL). The organic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicachromatography eluted with a gradient of 1-5% triethylamine in ethylacetate to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-2,6-diyl)diacetate (158 mg, 17% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.83 (d, 4H), 7.51 (dd, 2H), 6.79 (d, 2H),6.63 (d, 2H), 4.70 (s, 2H), 4.06 (s, 4H), 3.19 (d, 2H), 3.13-2.93 (m,4H), 2.70 (dd, 2H), 2.59 (dd, 2H), 2.47-2.28 (m, 8H), 2.22 (dt, 2H),1.88 (dt, 2H), 1.69-1.45 (m, 6H), 0.95-0.80 (m, 2H), 0.61-0.52 (m, 4H),0.18-0.11 (m, 4H). [M+H]⁺ 891.40.

1.3 Compound 3 Synthesis of 1,5-bis(allyloxy)naphthalene

To a solution of 1,5-dihydroxynaphtalene (10 g, 62 mmol) in acetone (55mL) and tetrahydrofuran (55 mL) were added potassium carbonate (21 g,149 mmol) and allyl bromide (13 mL, 149 mmol). The mixture was heated atreflux for 16 hours and diluted with ethyl acetate. The organic layerwas washed with 1 M aqueous solution of sodium hydroxide (100 mL), waterand brine, dried over magnesium sulfate, filtered and concentrated underreduced pressure to give a brown solid. The solid was triturated withhexane to give 1,5-bis(allyloxy)naphthalene (8.1 g, 54% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.89 (d, 2H), 7.35 (t, 2H), 6.84 (d, 2H),6.24-6.11 (m, 2H), 5.52 (d, 2H), 5.33 (d, 2H), 4.70 (d, 4H).

Synthesis of 2,6-diallylnaphthalene-1,5-diol

A suspension of 1,5-bis(allyloxy)naphthalene (6.1 g, 25 mmol) inanhydrous dodecane (15 mL) was degassed with argon and heated at 200° C.for 1 hour under an atmosphere of argon. The reaction was cooled down toroom temperature and the solid was triturated with hexane, filtered andwashed with hexane to give 2,6-diallylnaphthalene-1,5-diol (5.4 g, 88%yield).

¹H NMR (300 MHz, CDCl₃): δ 7.69 (d, 2H), 7.23 (d, 2H), 6.14-6.01 (m,2H), 5.48 (d, 2H), 5.27-5.21 (m, 4H), 3.58 (d, 4H).

Synthesis of 2,6-diallylnaphthalene-1,5-diyl Diacetate

To a solution of 2,6-diallylnaphthalene-1,5-diol (1.0 g, 4.1 mmol) indichloromethane (25 mL) were added triethylamine (2 mL, 14.5 mmol) andacetic anhydride (1.9 mL, 20.8 mmol). After stirring at room temperatureunder an atmosphere of argon for 16 hours, the reaction was quenchedwith water, extracted with dichloromethane (×2), dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica chromatography, eluted with 15% ethyl acetate inheptanes to give 2,6-diallylnaphthalene-1,5-diyl diacetate (1.1 g, 84%yield).

¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, 2H), 7.36 (d, 2H), 5.96-5.86 (m,2H), 5.13-5.08 (m, 4H), 3.41 (d, 4H), 2.45 (s, 6H).

Synthesis of 2,2′-(1,5-diacetoxynaphthalene-2,6-diyl)diacetic Acid

A solution of 2,6-diallylnaphthalene-1,5-diyl diacetate (1.1 g, 3.4mmol) in dichloromethane:methanol (20 mL:20 mL) was ozonolized at −78°C. for 10 minutes, then evaporated a low heat under reduced pressure todryness to give an orange gum. The residue was stirred in formic acid(15 mL) and aqueous hydrogen peroxide (35%, 8 mL) at room temperaturefor 16 hours. The reaction was quenched with water, extracted with ethylacetate (×3), dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was triturated with diethylether:heptane (1:1) to give2,2′-(1,5-diacetoxynaphthalene-2,6-diyl)diacetic acid (370 mg, 30%yield).

¹H NMR (300 MHz, CDCl₃): δ 7.69 (d, 2H), 7.52 (d, 2H), 3.67 (s, 4H),2.46 (s, 6H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-diacetoxynaphthalene-2,6-diyl)diacetate

To a solution of 2,2′-(1,5-diacetoxynaphthalene-2,6-diyl)diacetic acid(200 mg, 0.56 mmol) in dichloromethane (30 mL) and triethylamine (0.31mL, 2.22 mmol) were added naltrexone (375 mg, 1.11 mmol) and(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)(635 mg, 1.22 mmol) and stirred at room temperature under an atmosphereof argon for 3 hours. The reaction was quenched with brine, extractedwith dichloromethane (×2), dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (C18). The combined fractions were extracted withethyl acetate (×2), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a brown solid. The compoundwas repurified by silica chromatography, eluted with 50% dichloromethanein ethyl acetate (with 1% triethylamine) to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-diacetoxynaphthalene-2,6-diyl)diacetate (170 mg, 30% yield).

¹H NMR (400 MHz, CDCl₃): δ 7.69 (d, 2H), 7.59 (d, 2H), 6.77 (d, 2H),6.61 (d, 2H), 5.20 (br s, 2H), 4.68 (s, 2H), 3.95 (q, 4H), 3.18 (d, 2H),3.08-2.97 (m, 4H), 2.67 (dd, 2H), 2.57 (dd, 2H), 2.51 (s, 6H), 2.44-2.35(m, 6H), 2.31 (dt, 2H), 2.11 (td, 2H), 1.90-1.84 (m, 2H), 1.66-1.56 (m,4H), 0.90-0.80 (m, 2H), 0.57-0.52 (m, 4H), 0.11-0.15 (m, 4H). [M+H]⁺1007.59.

1.4 Compound 4 Synthesis of 2,6-diallyl-1,5-dimethoxynaphthalene

To a solution of 2,6-diallylnaphthalene-1,5-diol (1.0 g, 4.16 mmol) inanhydrous acetone (25 mL) were added potassium carbonate (1.2 g, 9.15mmol) followed by dimethyl sulfate (0.87 mL, 9.15 mmol) dropwise at roomtemperature under an atmosphere of argon and stirred at reflux for 16hours. The reaction was quenched with water, extracted with ethylacetate (×2), dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The compound was purified by silicachromatography, eluted with 5% ethyl acetate in heptane to give2,6-diallyl-1,5-dimethoxynaphthalene (915 mg, 83% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.81 (d, 2H), 7.32 (d, 2H), 6.09-5.98 (m,2H), 5.11-5.07 (m, 4H), 3.90 (s, 6H), 3.58 (d, 4H).

Synthesis of 2,2′-(1,5-dimethoxynaphthalene-2,6-diyl)diacetic Acid

To a mixture of 2,6-diallyl-1,5-dimethoxynaphthalene (600 mg, 2.23 mmol)in 1,4-dioxane (35 mL) and water (10 mL) were added sodium periodate(3.8 g, 17.8 mmol) and potassium osmate(VI) dehydrate (8.2 mg, 0.022mmol) and stirred vigorously at room temperature for 16 hours. Thereaction was filtered through a pad of celite, rinsed with ethylacetate, the filtrate was washed with water and the organic layer wasdried over magnesium sulfate, filtered and concentrated under reducedpressure to give a white solid. The residue was stirred intert-butanol:water (24 mL:15 mL) and 2-methyl-2-butene (18 mL), sodiumdihydrogen phosphate (3.7 g, 31.3 mmol) and sodium chlorite (3.6 g, 40.2mmol) were added. The mixture was stirred vigorously at room temperaturefor 4 hours and filtered through a pad of celite and rinsed with ethylacetate and 2-methyltetrahydrofuran. The filtrate was extracted withethyl acetate (×2) and concentrated under reduced pressure. The residuewas partitioned between a 2 M aqueous solution of sodium hydroxide andethyl acetate and the aqueous layer was extracted with ethyl acetate anddiethyl ether. The aqueous layer was acidified with a 2 M aqueoussolution of hydrochloric acid and extracted with 2-methyltetrahydrofuran(×2), dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was triturated with diethyl ether (×2) togive 2,2′-(1,5-dimethoxynaphthalene-2,6-diyl)diacetic acid (170 mg, 25%yield).

¹H NMR (300 MHz, CDCl₃): δ 7.79 (d, 2H), 7.41 (d, 2H), 3.90 (s, 6H),3.75 (s, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-dimethoxynaphthalene-2,6-diyl)diacetate

To a solution of 2,2′-(1,5-dimethoxynaphthalene-2,6-diyl)diacetic acid(170 mg, 0.56 mmol) in 2-methyltetrahydrofuran (50 mL) and triethylamine(0.31 mL, 2.23 mmol) were added naltrexone (897 mg, 2.62 mmol) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.5g, 2.88 mmol) and stirred at room temperature for 16 hours. The reactionwas quenched with brine, extracted with ethyl acetate (×2) anddichloromethane, dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by reverse phasechromatography (C18). The combined fractions were extracted with ethylacetate (×2), dried over magnesium sulfate, filtered and concentratedunder reduced pressure to give a yellow solid. The compound wasrepurified by silica chromatography, eluted with 40% dichloromethane inethyl acetate (with 1% triethylamine) to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-dimethoxynaphthalene-2,6-diyl)diacetate (179 mg, 33% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.89 (d, 2H), 7.53 (d, 2H), 6.83 (d, 2H),6.64 (d, 2H), 5.21 (br s, 2H), 4.68 (s, 2H), 4.13 (s, 4H), 4.01 (s, 6H),3.20-2.95 (m, 6H), 2.70-2.55 (m, 4H), 2.46-2.28 (m, 8H), 2.16-2.08 (m,2H), 1.90-1.85 (m, 2H), 1.66-1.53 (m, 4H), 0.92-0.82 (m, 2H), 0.57-0.54(m, 4H), 0.15-0.13 (m, 4H). [M+H]⁺ 951.32.

1.5 Compound 5 Synthesis of 1,5-difluoronaphtalene

To a suspension of 1,5-diaminonaphthalene (5.0 g, 31.6 mmol) intetrahydrofuran (12 mL) was added slowly fluoroboric acid (50% in water,140 mL) at −10° C. followed by a solution of sodium nitrite (18 g, 260mmol) in water (60 mL) over 45 minutes. The mixture was stirred at −10°C. for 1 hour and sodium tetrafluoroborate (35 g, 318 mmol) was addedportionwise. The reaction was stirred at room temperature for 1.5 hours.The solid was filtered, rinsed with diethyl ether (500 mL) and driedunder vacuum in a dessicator overnight. The solid was suspended inxylenes and heated at reflux for 1 hour. The reaction was concentratedcarefully under vacuum and the residue was diluted with dichloromethaneand filtered through a pad of celite which was rinsed withdichloromethane and the filtrate was evaporated carefully under reducedpressure. The residue was purified by silica chromatography eluted with2% ethyl acetate in heptanes followed by reverse phase chromatography(C18). The desired fractions were combined and acetonitrile wasevaporated under reduced pressure. The aqueous layer was extracted withethyl acetate (×2), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give 1,5-difluoronaphtalene (1.6g, 32% yield).

¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, 2H), 7.46 (ddd, 2H), 7.21 (ddd, 2H).¹⁹F NMR (282 MHz, CDCl₃): δ −121.4.

Synthesis of 2,6-dibromo-1,5-difluoronaphtalene

To a solution of 1,5-difluoronaphtalene (877 mg, 5.34 mmol) in anhydroustetrahydrofuran (90 mL) and anhydrous tetramethylethylenediamine (3.3mL, 21.3 mmol) was added slowly sec-butyllithium (1.2 M in cyclohexane,17 mL, 20.4 mmol) at −78° C. under an atmosphere of argon. The solutionwas stirred at −78° C. for 2 hours and bromine (1.7 mL, 32.0 mmol) wasadded slowly. The mixture was warmed up slowly to room temperature over2 hours and quenched with an aqueous solution of ammonium chloride. Themixture was extracted with ethyl acetate (×2) and the combined organiclayers were washed with a 10% aqueous solution of sodium thiosulfate,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by reverse phase chromatography(C18). The desired fractions were combined and acetonitrile wasevaporated under reduced pressure. The aqueous layer was extracted withethyl acetate (×2), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give2,6-dibromo-1,5-difluoronaphtalene (284 mg, 16% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 2H), 7.64 (dd, 2H).

Synthesis of dimethyl 2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetate

To a solution of 2,6-dibromo-1,5-difluoronaphtalene (234 mg, 0.73 mmol)in degassed anhydrous dimethylformamide (4.8 mL) were addedtris(dibenzyllideneacetone)dipalladium(0) (208 mg, 0.36 mmol),tributylphosphine (1M in toluene, 0.22 mL, 0.22 mmol) and1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.63 mL, 2.90 mmol). Thereaction mixture was flushed with argon and irradiated at 120° C. for 1hour. Further 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.31 mL,1.45 mmol) was added and the mixture was irradiated at 120° C. for 1hour. The mixture was filtered through a pad of celite and rinsed withethyl acetate. The filtrate was washed with water (×3), dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by reverse phase chromatography (C18). The desiredfractions were combined and acetonitrile was evaporated. The aqueouslayer was extracted with ethyl acetate (×2), dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The compoundwas purified further by silica chromatography eluted with 30% ethylacetate in heptanes to give dimethyl2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetate (90 mg, 33% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.83 (d, 2H), 739 (dd, 2H), 3.85 (s, 4H),3.72 (s, 6H). ¹⁹F NMR (300 MHz, CDCl₃): δ −125.9.

Synthesis of 2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetic Acid

To a solution of dimethyl2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetate (90 mg, 0.291 mmol) in amixture of tetrahydrofuran (8 mL) and water (4 mL) was added lithiumhydroxide monohydrate (37 mg, 0.881 mmol). After stirring for 4 hours atroom temperature, the mixture was diluted with water and washed withdiethyl ether. The aqueous layer was acidified with a 2 M aqueoussolution of hydrochloric acid and extracted with 2-methyltetrahydrofuran(×3). The combined organic layers were dried over magnesium sulfate andconcentrated under reduced pressure to give a solid which was trituratedwith diethyl ether to afford2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetic acid (62 mg, 76% yield).

¹H NMR (400 MHz, DMSO-d₆): δ 7.78 (d, 2H), 7.53 (dd, 2H), 3.80 (s, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-difluoronaphthalene-2,6-diyl)diacetate

To a suspension of 2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetic acid(65 mg, 0.231 mmol) in 2-methyltetrahydrofuran (15 mL) and triethylamine(0.13 mL, 0.924 mmol) were added naltrexone (158 mg, 0.462 mmol) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (264mg, 0.507 mmol). The mixture was stirred at room temperature for 2hours, quenched with brine and extracted with ethyl acetate (×3). Thecombined organic layers were dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (C18). The combined fractions were extracted withethyl acetate (×2), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-difluoronaphthalene-2,6-diyl)diacetate (70 mg, 32% yield).

¹H NMR (400 MHz, CDCl₃): δ 7.87 (d, 2H), 7.54 (dd, 2H), 6.82 (d, 2H),6.64 (d, 2H), 5.19 (br s, 2H), 4.70 (s, 2H), 4.14 (s, 4H), 3.19 (d, 2H),3.09-2.97 (m, 4H), 2.68 (dd, 2H), 2.59 (dd, 2H), 2.44-2.37 (m, 6H), 2.32(dt, 2H), 2.10 (td, 2H), 1.90-1.86 (m, 2H), 1.66-1.56 (m, 4H), 0.90-0.81(m, 2H), 0.57-0.52 (m, 4H), 0.15-0.11 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃):δ −125.4. [M+H]+ 927.40.

1.6 Compound 6 Synthesis of 1,5-dichloronaphthalene-2,6-diol

To a solution of naphthalene-2,6-diol (3.0 g, 18.7 mmol) in acetic acid(90 mL) was added sulfuryl chloride (3.0 mL, 37.5 mmol) dropwise and themixture stirred at room temperature for 3 hours. Water (50 mL) was addedto the reaction flask and the mixture stirred for 10 minutes. The greycoloured solid which precipitates out of solution was filtered off andwashed with water (3×50 mL) and heptane (3×30 mL), notably under aninverted funnel with continuous nitrogen flow over the solid to preventoxidation. The light grey solid was quickly transferred to a flask andleft under vacuum overnight to dry, to afford1,5-dichloronaphthalene-2,6-diol as a light grey solid (2.65 g, 62%yield).

¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, 2H), 7.34 (d, 2H), 5.79 (s, 2H, OH).

Synthesis of 1,5-dichloronaphthalene-2,6-diylbis(trifluoromethanesulfonate)

To a suspension of 1,5-dichloronaphthalene-2,6-diol (2.65 g, 11.6 mmol)in dichloromethane (100 mL), cooled in an ice bath, was added pyridine(5.61 mL, 69.4 mmol) to give a brown solution. Using a dropping funnel,trifluoromethanesulfonic anhydride (4.3 mL, 25.4 mmol) was addeddropwise over 20 minutes. After completion of the addition, the ice bathwas removed and the reaction mixture stirred for 18 hours at roomtemperature. Water (30 mL) was added to the mixture followed by aq. 2Mhydrochloric acid (20 mL) with stirring. The layers were separated anddichloromethane layer washed with aqueous 1 M hydrochloric acid (3×100mL), water (30 mL) and aqueous sodium hydrogen carbonate (30 mL). Thedichloromethane layer was passed through a phase separator andconcentrated under reduced pressure to afford a grey solid (3.84 g). Thecrude solid was re-dissolved in dichloromethane and absorbed onto silicaand purified by flash chromatography (C18 cartridge) eluting withdichloromethane to afford 1,5-dichloronaphthalene-2,6-diylbis(trifluoromethanesulfonate) as a white solid (2.0 g, 35% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.39 (d, 2H), 7.66 (d, 2H). ¹⁹F NMR (372 MHz,CDCl₃): δ −73.11 (s).

Synthesis of dimethyl 2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetate

To a solution of 1,5-dichloronaphthalene-2,6-diylbis(trifluoromethanesulfonate) (1.99 g, 4.03 mmol) in 1,4-dioxane(degassed by vacuum/nitrogen purge×3), was added lithium acetate (1.06g, 16.1 mmol), tetrakis(triphenylphosphine)palladium(0) (466 mg, 0.40mmol) and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (3.04 g, 16.1mmol) and the mixture heated at 100° C. for 18 hours. The reactionmixture was cooled and diluted with water (100 mL) followed byextraction with tert-butylmethyl ether (3×30 mL). The organic layer waswashed with water (30 mL) and aqueous ammonium chloride (30 mL), dried(magnesium sulfate), filtered then absorbed onto silica and purified byflash column chromatography eluting with 10% ethylacetate in heptane toafford dimethyl 2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetate as awhite solid (422 mg, 31% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.23 (d, 2H), 7.49 (d, 2H), 3.99 (s, 4H),3.70 (s, 6H).

Synthesis of 2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetic

To a solution of dimethyl2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetate (420 mg, 1.23 mmol) intetrahydrofuran (30 mL) and methanol (4 mL) was added aq. 2 M sodiumhydroxide (4 mL, 8 mmol) and stirred at room temperature overnight. Thesolvent was evaporated under reduced pressure to give a residue whichwas dissolved in water (30 mL). Additional aqueous 2 M sodium hydroxide(2 mL) was added and the aqueous layer washed with tert-butylmethylether (20 mL). The aqueous layer was carefully acidified with stirringusing aq. 2M hydrochloric acid. The white solid formed was filtered offand washed with water, triturated with tert-butylmethyl ether and airdried to afford 2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetic acid asa white solid (305 mg, 79% yield).

¹H NMR (400 MHz, DMSO-d₆): δ 12.66 (br.s, 2H), 8.20 (d, 2H), 7.72 (d,2H), 3.98 (s, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetate

To a suspension of 2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetic acid(150 mg, 0.48 mmol) in dry tetrahydrofuran (15 mL) under nitrogen, wasadded naltrexone (327 mg, 0.96 mmol), triethylamine (0.20 mL, 1.44 mmol)and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(548 mg, 1.05 mmol) and the mixture was stirred at room temperature for4 hours. The solvent was removed and the green residue re-dissolved inethylacetate (20 mL) and washed with water (20 mL), aqueous ammoniumchloride (3×20 mL), dried (magnesium sulfate), filtered and concentratedunder reduced pressure to give a crude solid. The solid was trituratedwith tert-butylmethyl ether followed with further purification byreverse phase chromatography (C18 cartridge), eluting with a gradient of20-90% acetonitrile in 0.1% aq. ammonium formate buffer. The appropriatefractions were combined and partially concentrated under reducedpressure and extracted with ethylacetate (3×30 mL). The organic layerwas washed with aqueous ammonium chloride (30 mL). The aqueous layer wasre-extracted with dichloromethane (2×30 mL) and washed with aqueousammonium chloride. Both organic layers were combined, dried (magnesiumsulfate), filtered, and concentrated under reduced pressure. The productwas co-evaporated with acetonitrile, to remove traces of solvent, toaffordbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-dichloronaphthalene-2,6-diyl)diacetate as a white solid (182mg, 40% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.28 (d, 2H), 7.66 (d, 2H), 6.83 (d, 2H),6.65 (d, 2H), 4.70 (s, 2H), 4.27 (s, 4H), 3.19 (br. s, 2H), 3.04 (d,2H), 2.98 (dt, 2H), 2.67 (br. d, 2H), 2.61 (dd, 2H), 2.33 (overlapped m,8H), 2.11 (dt, 2H), 1.89 (dt, 2H), 1.58 (overlapped m, 4H), 0.85 (m,2H), 0.54 (d, 4H), 0.14 (d, 4H). [M³⁵Cl/³⁷Cl]⁺ 959.02/961.11.

1.7 Compound 7 Synthesis of1,5-dibromo-2,6-bis(methoxymethoxy)naphthalene

To a solution of 1,5-dibromonaphthalene-2,6-diol (5.0 g, 15.73 mmol) indichloromethane (100 mL) was added diisopropylethylamine (16.43 mL) andthe reaction was cooled at 0° C. in water/ice bath. To the reactionmixture was added chloromethyl methyl ether (7.17 mL) via a syringe anddropwise over 5 minutes. The reaction was left to stir for 18 hours.After this time the reaction was diluted with water (100 mL) anddichloromethane (100 mL). The organic was separated and the aqueousre-extracted with dichloromethane (100 mL). The combined organics werewashed with brine (150 mL), filtered through a phase separator andreduced to dryness to give brown gum. The gum was triturated withheptane to give a pale brown solid which was filtered to give1,5-dibromo-2,6-bis(methoxymethoxy)naphthalene as yellow solid (5.79,91%).

¹H NMR (396 MHz, DMSO-d₆): δ 8.12 (d, 2H), 7.63 (d, 2H), 5.38 (s, 4H),3.42 (s, 6H).

Synthesis of 2,6-bis(methoxymethoxy)-1,5-dimethylnaphthalene

To a solution of 1,5-dibromo-2,6-bis(methoxymethoxy)naphthalene (1.50 g,3.69 mmol) in dioxane (75 mL) was added potassium carbonate (1.53 mg,11.08 mmol) and trimethylboroxine (2.78 g, 22.16 mmol). The mixture wasdegassed (cycle vacuum-nitrogen ×3) and thenpalladium-tetrakis(triphenylphosphine) (213 mg, 0.185 mmol) was addedbefore degassing again with vacuum-nitrogen cycles three time. Thereaction was heated at reflux 18 hours. The reaction was cooled to roomtemperature, diluted with sodium hydrogen carbonate (150 mL) andextracted with ethylacetate (100 mL×3). The combined organics werewashed with brine (150 mL), dried over sodium sulfate, filtered andreduced to dryness to give a brown solid (1.319 g). The crude wasabsorbed onto silica and purified by silica column chromatography(dichloromethane:heptane=1:1 to 7:3). The correct fractions werecollected and reduced to dryness to give2,6-bis(methoxymethoxy)-1,5-dimethylnaphthalene as colourless solid (800mg, 78%).

¹H NMR (396 MHz, CDCl₃): δ 7.80 (d, 2H), 7.38 (d, 2H), 5.25 (s, 4H),3.53 (s, 6H), 2.56 (s, 6H).

Synthesis 1,5-dimethylnaphthalene-2,6-diol

2,6-Bis(methoxymethoxy)-1,5-dimethylnaphthalene (581 mg, 2.10 mmol) wasdissolved in hydrochloric acid 4.0 M dioxane (30 mL) and the reactionstirred at room temperature for 3 hours, the formation of someprecipitate was observed. After completion the reaction was reduced todryness to give 1,5-dimethylnaphthalene-2,6-diol as pale yellow solid(472 mg, quantitative).

¹H NMR (396 MHz, DMSO-d₆): δ 9.06 (s, 2H), 7.57 (d, 2H), 7.10 (d, 2H),2.36 (s, 6H).

Synthesis 1,5-dimethylnaphthalene-2,6-diylbis(trifluoromethanesulfonate)

1,5-Dimethylnaphthalene-2,6-diol (395 mg, 2.10 mmol, expected amount,amount from hydrolysis 490 mg) was suspended in dichloromethane (25 mL).Dry triethylamine (637 mg, 6.30 mmol, 0.88 mL) was added at 0° C.Triflic anhydride (1.48 g, 5.25 mmol, 0.88 mL) was added over 10 minutesand the reaction stirred for 5 min and then checked by LC. Drytriethylamine (319 mg, 3.15 mmol, 0.44 mL) was added at 0° C. Triflicanhydride (740 mg, 2.62 mmol, 0.44 mL) was added and the reactionstirred for 5 min and then checked by LC The reaction was quenched byaddition of water (70 mL) and diluted with dichloromethane (30 mL). Theorganic was separated and the aqueous was extracted with dichloromethane(60 mL×2). The combined organics were washed with brine (60 mL),filtered through a phase separator and reduced to dryness to give abrown solid. The crude was absorbed onto silica and purified by silicacolumn chromatography (dichloromethane:heptane=4:6). The correctfractions were collected and reduced to dryness to give the titlecompound as colourless solid (730 mg, 76%).

¹H NMR (396 MHz, CDCl₃): δ 8.02 (d, 2H), 7.50 (d, 2H), 2.72 (s, 6H). ¹⁹FNMR (372 MHz, CDCl₃): δ −73.47.

Synthesis of dimethyl 2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetate

To a solution of 1,5-dimethylnaphthalene-2,6-diylbis(trifluoromethanesulfonate) (730 mg, 1.61 mmol) in dioxane (18 mL)was added lithium acetate (639 g, 9.68 mmol),tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (1.82 g, 9.68 mmol) andpalladium-tetrakis(triphenylphosphine) (186 mg, 0.161 mmol). The mixturewas degassed (cycle vacuum-nitrogen×3) and then heated at reflux for 3hours. The reaction was allowed to cool to room temperature, water (200mL) was added and the aqueous extracted with ethylacetate (3×60 mL). Thecombined organics were washed with brine (150 mL), dried over magnesiumsulfate, filtered and reduced to dryness to give a black solid. Thecrude was absorbed onto silica and purified by silica columnchromatography (dichloromethane). The correct fractions were collectedand reduced to dryness to give dimethyl2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetate as a colourless solid(299 mg, 62%).

¹H NMR (396 MHz, CDCl₃): δ 7.92 (d, 2H), 7.37 (d, 2H), 3.86 (s, 4H),3.68 (s, 6H), 2.63 (s, 6H).

Synthesis of 2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetic Acid

To a solution of dimethyl2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetate (299 mg, 0.995 mmol) intetrahydrofuran:methanol (1:1, 50 mL) was added 1.0 M lithium hydroxide(95.3 mg, 3.98 mmol) and the reaction stirred at room temperature for 18hours. Lithium hydroxide 1.0 M (95.3 mg, 3.98 mmol) was added and thereaction stirred for 4 hours. The reaction was reduced to dryness,2-methyltetrahydrofuran (30 mL) was added and the reaction acidified byaddition of hydrochloric acid 2.0 M (15 mL) and then water (15 mL). Theorganic was separated and the aqueous was re-extracted with 2-methyltetrahydrofuran (50 mL). The combined organics were dried over sodiumsulfate, filtered and reduced to dryness to give2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetic acid as a pale creamsolid (300 mg, quantitative).

¹H NMR (396 MHz, DMSO-d₆): δ 12.28 (s, 2H), 7.85 (d, 2H), 7.34 (d, 2H),3.77 (s, 4H), 2.50 (s, 6H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetate

To a suspension of 2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetic acid(231 mg, 0.848 mmol) in tetrahydrofuran (dry, 25 mL) was addedtriethylamine (343 mg, 3.39 mmol, 0.473 mL) and naltrexone (579 mg, 1.70mmol). To the mixture was then added(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (106mg, 2.04 mmol) and the reaction left to stir at room temperature for 15minutes. The reaction was quenched with water (80 mL) and extracted withethylacetate (3×80 mL). The combined organics were washed with brine(100 mL), dried over sodium sulfate, filtered and reduced to dryness.The crude was purified on reverse phase usingwater/acetonitrile+ammonium carbonate pH 9 buffer, 30% acetonitrile to100%. The correct fractions were combined, extracted with ethyl acetateand washed with brine (150 mL), dried over sodium sulfate, filtered, andreduced to dryness to give bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(1,5-dimethylnaphthalene-2,6-diyl)diacetate as a colourless foamafter co-evaporation with dichloromethane (488 mg, 63%).

¹H NMR (396 MHz, DMSO-d₆): δ 7.98 (d, 2H), 7.52 (d, 2H), 6.82 (d, 2H),6.71 (d, 2H), 5.14 (s, 2H), 4.93 (s, 2H), 4.21 (s, 4H), 3.16 (d, 2H),3.06 (d, 2H), 2.91 (td, 2H), 2.72-2.52 (m, 10H), 2.44-2.27 (m, 6H),2.15-2.05 (m, 2H), 1.93 (td, 2H), 1.78 (ddd, 2H), 1.44 (td, 2H),1.32-1.21 (m, 2H), 0.93-0.79 (m, 2H), 0.54-0.39 (m, 4H), 0.11 (m, 4H).[M+H]+ 919.40.

1.8 Compound 8 Synthesis of dimethyl3,3′-(naphthalene-2,6-diyl)(2E,2′E)-diacrylate

To a solution of 2,6-dibromonaphthalene (1.0 g, 3.49 mmol) in degasseddioxane (16 mL) was added methyl acrylate (6.3 mL, 69.9 mmol) followedby N,N-dicyclohexylmethylamine (3.3 mL, 15.4 mmol) andbis(tri-tert-butylphosphine)palladium(0) (71 mg, 0.13 mmol). Thereaction mixture was heated at 90° C. for 16 hours then cooled to roomtemperature, concentrated under reduced pressure and diluted withdichloromethane. The organic layer was washed with 0.5 M aqueoussolution of hydrochloric acid (×2), saturated aqueous solution of sodiumhydrogen carbonate and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting yellow solid wastriturated with ethyl acetate followed by water. The solid was thenwashed with heptane and diethyl ether to give dimethyl3,3′-(naphthalene-2,6-diyl)(2E,2′E)-diacrylate as a white solid (376 mg,36% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.91-7.81 (m, 6H), 7.69 (d, 2H), 6.57 (d,2H), 3.84 (s, 6H).

Synthesis of dimethyl 3,3′-(naphthalene-2,6-diyl)dipropionate

To a mixture of dimethyl 3,3′-(naphthalene-2,6-diyl)(2E,2′E)-diacrylate(370 mg, 1.25 mmol) and 10% palladium on carbon (80 mg) under anatmosphere of argon was added methanol (12 mL) and tetrahydrofuran (4mL). The reaction mixture was stirred under a hydrogen atmosphere atroom temperature for 18 hours. The reaction mixture was filtered througha pad of celite and rinsed with tetrahydrofuran and dichloromethane. Thefiltrate was concentrated under reduced pressure to give dimethyl3,3′-(naphthalene-2,6-diyl)dipropionate as a white solid (308 mg, 82%).

¹H NMR (300 MHz, CDCl₃): δ 7.71 (d, 2H), 7.60 (s, 2H), 7.31 (dd, 2H),3.67 (s, 6H), 3.10 (t, 4H), 2.71 (t, 4H).

Synthesis of 3,3′-(naphthalene-2,6-diyl)dipropionic Acid

To a suspension of dimethyl 3,3′-(naphthalene-2,6-diyl)dipropionate (300mg, 1.0 mmol) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2mL) was added lithium hydroxide monohydrate (350 mg, 8.0 mmol). Thereaction mixture was stirred at room temperature for 3 hours.Tetrahydrofuran and methanol were removed under reduced pressure; themixture was then diluted with water and cooled to 5° C. beforeacidifying with 2 M aqueous solution of hydrochloric acid. The resultingsolid was filtered, washed with water, heptane, acetonitrile and diethylether and dried to give 3,3′-(naphthalene-2,6-diyl)dipropionic acid as awhite solid (172 mg, 63% yield).

¹H NMR (300 MHz, DMSO-d₆): δ 7.72 (d, 2H), 7.64 (s, 2H), 7.34 (d, 2H),3.94 (t, 4H), 2.59 (t, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)3,3′-(naphthalene-2,6-diyl)dipropionate

To a suspension of 3,3′-(naphthalene-2,6-diyl)dipropionic acid (170 mg,0.62 mmol) in anhydrous tetrahydrofuran (8 mL), was added triethylamine(0.35 mL, 2.49 mmol), naltrexone (469 mg, 1.37 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (779mg, 1.50 mmol). The reaction mixture was stirred at room temperature for1 hour and then diluted with ethyl acetate and washed with saturatedaqueous solution of sodium hydrogencarbonate and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by reverse phasechromatography (C18). Selected fractions were partitioned between ethylacetate and brine. The layers were separated, aqueous layer wasextracted with ethyl acetate (×2), dried over sodium sulfate, filteredand concentrated under reduced pressure to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)3,3′-(naphthalene-2,6-diyl)dipropionate as a white solid (240 mg, 42%yield).

¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 2H), 7.68 (s, 2H), 7.38 (dd, 2H),6.74 (d, 2H), 6.64 (d, 2H), 5.21 (br. s, 2H), 4.70 (s, 2H), 3.25-3.19(m, 6H), 3.11-2.92 (m, 8H), 2.70 (dd, 2H), 2.60 (dd, 2H), 2.48-2.29 (m,8H), 2.14 (td, 2H), 1.92-1.85 (m, 2H), 1.69-1.58 (m, 4H), 0.91-0.81 (m,2H), 0.59-0.53 (m, 4H), 0.15 (q, 4H). [M+H]+ 919.39.

1.9 Compound 9 Synthesis of di-tert-butyl2,2′-(naphthalene-1,8-diyl)diacetate

To tris(dibenzylideneacetone)dipalladium(0) (160 mg, 0.17 mmol) inN,N-dimethylformamide (20 mL) was added a solution oftri-tert-butylphosphine (0.35 mL, 0.35 mmol, 1M in toluene) and degassedby vacuum/nitrogen purge ×3. To this red/brown solution was added((1-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethyl silane (2.42 g, 10.5mmol), 1,8-dibromonaphthalene (1.0 g, 3.5 mmol) and zinc fluoride (181mg, 1.75 mmol). The mixture was heated at 110° C. for 18 hours. Startingmaterial was still present (ca. 39%) so additionaltris(dibenzylideneacetone)dipalladium(0) (90 mg, 0.10 mmol),((1-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (2.42 g, 10.5mmol) and zinc fluoride (181 mg, 1.75 mmol) was added. The mixture washeated at 110° C. for a further 18 hours then the reaction mixture wascooled and poured onto aqueous ammonium chloride (150 mL) and productextracted with tert-butylmethyl ether (2×60 mL). Notably the emulsionrequired addition of Dicalite filter aid followed by filtration toremove inorganic impurities. The combined organic layer was washed withwater (60 mL) and aqueous ammonium chloride (60 mL) and dried (magnesiumsulfate). Solvent was removed under reduced pressure to afford a crudered/brown oil (3.5 g). The crude material was absorbed onto silica andpurified by flash column chromatography eluting with 0-5%tert-butylmethyl ether-heptane to afford di-tert-butyl2,2′-(naphthalene-1,8-diyl)diacetate as a yellow solid (303 mg, 24%yield).

¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, 2H), 7.31-7.38 (m, 4H), 4.08 (s,4H), 1.43 (s, 18H).

Synthesis of 2,2′-(naphthalene-1,8-diyl)diacetyl Chloride

Into a capped vessel, di-tert-butyl 2,2′-(naphthalene-1,8-diyl)diacetate(231 mg, 0.65 mmol) was dissolved in thionyl chloride (3 mL). Water (23mg, 23 μL, 1.29 mmol) was added and the vessel immediately capped andsealed. The mixture was stirred at room temperature for 18 hours. Thecap was removed (some pressure observed) the contents were transferredto a round-bottom flask and solvent was removed by co-evaporation withdichloromethane three times, under reduced pressure to afford ared/brown colored residue (504 mg). The crude was dissolved indichloromethane and passed through a short pad of silica eluting withdichloromethane. The solvent was removed under reduced pressure toafford 2,2′-(naphthalene-1,8-diyl)diacetyl chloride (365 mg) which wasused directly in the next step.

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-1,8-diyl)diacetate

To a solution of 2,2′-(naphthalene-1,8-diyl)diacetyl chloride (365 mg,0.65 mmol) in dry dichloromethane (10 mL) was added naltrexone (444 mg,1.3 mmol) and stirred at room temperature for 3.5 hours. To thesuspension was added triethylamine (0.27 mL, 1.95 mmol) followed bywater (5 mL) and aqueous ammonium chloride (10 mL). The dichloromethanelayer was passed through a phase separator and the solvent removed underreduced pressure to afford a crude brown solid. It was re-dissolved indichloromethane, absorbed onto silica and purified by flash columnchromatography eluting with 50-100% ethylacetate in heptane. The desiredfraction were concentrated to dryness and the solid was furtherre-crystallized from ethylacetate/tert-butylmethyl ether and heptane toaffordbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-1,8-diyl)diacetate as a white solid (150 mg, 26%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (d, 2H), 7.61 (d, 2H), 7.52 (t, 2H),6.83 (d, 2H), 6.72 (d, 2H), 5.14 (s, 2H), 4.94 (s, 2H), 4.62 (q, 4H),3.16 (d, 2H), 3.07 (d, 2H), 2.91 (dt, 2H), 2.62 (m, 4H), 2.36 (m, 6H),2.12 (br.d, 2H), 1.92 (br.t, 2H), 1.77 (br.d, 2H), 1.44 (t, 2H), 1.24(br.d, 2H), 0.86 (m, 2H), 0.49 (d, 4H), 0.13 (d, 4H). [M+H]⁺ 891.40.

1.10 Compound 10 Synthesis of di-tert-butyl2,2′-(naphthalene-2,7-diyl)diacetate

To a suspension of 1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-iumchloride (8.5 mg, 0.02 mmol), palladium(0) bis(dibenzylideneacetone)₂(12 mg, 0.02 mmol) and lithium bis(trimethylsilyl)amide (4.6 mL, 1 Msol. in toluene, 4.6 mmol) were added sequentially2,7-dibromonaphthalene (0.29 g, 1.0 mmol) and tert-butylacetate (0.30mL, 2.2 mmol). The reaction mixture was stirred at room temperature for3 days, and then was reduced to dryness in vacuo. The crude material waspurified by normal phase chromatography (10% ethylacetate in heptane) togive the desired compound di-tert-butyl2,2′-(naphthalene-2,7-diyl)diacetate as off white solid (160 mg, 45%yield).

¹H NMR (400 MHz, DMSO-d₆): δ 7.84 (d, 2H), 7.71 (s, 2H), 7.37 (d, 2H),3.72 (s, 4H), 1.40 (s, 18H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-2,7-diyl)diacetate

A solution of di-tert-butyl 2,2′-(naphthalene-2,7-diyl)diacetate (100mg, 0.28 mmol) and water (0.01 mL, 0.56 mmol) in thionyl chloride (0.81mL) was stirred overnight in a sealed vial. The reaction mixture wasreduced to dryness in vacuum to give the di-acid chloride as a brownsolid (acid chloride was used in the next step without furtherpurification). To a solution of naltrexone (0.20 g, 0.59 mmol) andtriethylamine (0.1 mL, 0.70 mmol) in dichloromethane (4 mL) was added asolution of the di-acid chloride (prepared above) (75 mg, 0.27 mmol) indichloromethane (2 mL) dropwise over 5 min. The resulting brown mixturewas stirred overnight under an atmosphere of nitrogen. The reactionmixture was concentrated in vacuo and the crude material was purified bynormal phase chromatography (SiO₂, eluting 10% acetone indichloromethane (1% triethylamine) to give the desired compoundbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(naphthalene-2,7-diyl)diacetate as off-white solid (75 mg, 34%yield).

¹H NMR (400 MHz, CDCl₃): δ 7.84 (s, 2H), 7.82 (d, 2H), 7.51 (d, 2H),6.78 (d, 2H), 6.43 (d, 2H), 4.71 (s, 2H), 4.07 (s, 4H), 3.21 (d, 2H),3.07 (d, 2H), 3.02 (td, 2H), 2.70 (dd, 2H), 2.68 (dd, 2H), 2.48-2.28 (m,8H), 2.12 (td, 2H), 1.94-1.83 (m, 2H), 1.69-1.55 (m, 4H), 0.92-0.79 (m,2H), 0.60-0.51 (m, 4H), 0.17-0.09 (m, 4H). [M+H]⁺ 891.40.

1.11 Compound 2i Synthesis of2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)naphthalen-2-yl)aceticAcid

To a solution of 2,2′-(naphthalene-2,6-diyl)diacetic acid (2 g, 8.19mmol) in tetrahydrofuran (140 mL) was added triethylamine (2.3 mL, 16.38mmol), benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (5.11 g, 9.82 mmol) and naltrexone (2.79 g, 8.19mmol). The reaction mixture was stirred at ambient temperature for 16hours then concentrated under reduced pressure. The residue was purifiedby reverse phase chromatography (C₁₈). The material obtained wastriturated with diethyl ether (×2) to give2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)naphthalen-2-yl)aceticacid (1.01 g, 22%).

¹H NMR (300 MHz, CDCl₃): δ 7.80-7.71 (m, 4H), 7.46 (dd, 1H), 7.42 (dd,1H), 6.76 (d, 1H), 6.59 (d, 1H), 5.97 (br s, 2H), 4.66 (s, 1H), 4.03 (s,2H), 3.76 (s, 2H), 3.27 (d, 1H), 3.07-2.99 (m, 2H), 2.78 (dd, 1H),2.66-2.40 (m, 4H), 2.27 (dt, 1H), 2.10 (td, 1H), 1.92-1.84 (m, 1H),1.62-1.49 (m, 2H), 0.91-0.79 (m, 1H), 0.55-0.48 (m, 2H), 0.12 (q, 2H).[M+H]⁺ 568.33.

1.12 Compound 4i Synthesis of2-(6-(2-(tert-butoxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)aceticAcid

To a suspension of 2,2′-(1,5-dimethoxynaphthalene-2,6-diyl)diacetic acid(277 mg, 0.91 mmol) in tert-butyl alcohol (40 mL) and tetrahydrofuran(40 mL) was added 4-dimethylaminopyridine (55 mg, 0.45 mmol), then asolution of di-tert-butyl dicarbonate (190 mg, 0.87 mmol) intetrahydrofuran (0.5 mL). The reaction mixture was heated at 75° C.overnight then cooled to room temperature and quenched with a saturatedaqueous ammonium chloride solution and extracted with ethyl acetate. Theorganic layers were dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (C₁₈) to give2-(6-(2-(tert-butoxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)aceticacid (25 mg, 7% yield) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.85 (dd, 2H), 7.40 (dd, 2H), 3.96 (s, 3H),3.93 (s, 3H), 3.89 (s, 2H), 3.74 (s, 2H), 1.47 (s, 9H).

Synthesis tert-butyl2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)acetate

To a solution of2-(6-(2-(tert-butoxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)aceticacid (25 mg, 0.069 mmol) and triethylamine (0.03 mL, 0.207 mmol) intetrahydrofuran (5 mL) was added naltrexone (23 mg, 0.069 mmol) followedby (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(40 mg, 0.076 mmol). The reaction mixture was stirred at roomtemperature under an atmosphere of argon for 4 hours. The reactionmixture was quenched with brine and a saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by reverse phasechromatography (C18). Appropriate fractions were combined andconcentrated under reduced pressure then extracted with ethyl acetate,dried over magnesium sulfate, filtered and concentrated under reducedpressure to give tert-butyl2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)acetate(30 mg, 63% yield) as a white solid. [M+H]⁺ 684.91.

Synthesis of2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)aceticAcid

tert-Butyl2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)acetate(30 mg, 0.044 mmol) and trifluoroacetic acid (0.4 mL) in dichloromethane(1 mL) were stirred at room temperature for 4 hours. The reactionmixture was then concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (C18). Appropriate fractionswere combined and organic solvent was concentrated under reducedpressure then freeze dried to give2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-dimethoxynaphthalen-2-yl)aceticacid (23 mg, 83% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.78 (dd, 2H), 7.52 (d, 1H), 7.43 (d, 1H),6.83 (d, 1H), 6.69 (d, 1H), 4.89 (s, 1H), 4.10 (s, 2H), 3.90 (s, 3H),3.82 (s, 3H), 3.73 (s, 2H), 3.18-2.97 (m, 2H), 2.88 (td, 1H), 2.72-2.50(m, 3H), 2.44-2.25 (m, 3H), 2.13-2.01 (m, 1H), 1.98-1.85 (m, 1H),1.81-1.69 (m, 1H), 1.50-1.33 (m, 1H), 1.31-1.17 (m, 1H), 0.82-0.76 (m,1H), 0.46 (d, 2H), 0.10 (d, 2H). [M+H]⁺ 628.26.

1.13 Compound 5i Synthesis of2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-difluoronaphthalen-2-yl)aceticAcid

To a suspension of 2,2′-(1,5-difluoronaphtalene-2,6-diyl)diacetic acid(200 mg, 0.71 mmol) in anhydrous tetrahydrofuran (25 mL) were addedtriethylamine (0.20 mL, 1.42 mmol),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (445mg, 0.86 mmol) and naltrexone (243 mg, 0.71 mmol) and the reactionmixture was stirred at room temperature under an atmosphere of argon for16 hours. The reaction was concentrated and purified by reverse phasechromatography (C18). The desired fractions were combined and freezedried as quickly as possible to give a white solid. This was dissolvedin a minimum of dichloromethane and triturated in diethyl ether:heptanes(1:1) to afford2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)-1,5-difluoronaphthalen-2-yl)aceticacid (100 mg, 23% yield).

¹H NMR (400 MHz, CDCl₃): δ 7.83 (dd, 2H), 7.53 (dd, 1H), 7.40 (dd, 1H),6.82 (d, 1H), 6.64 (d, 1H), 4.70 (s, 1H), 4.12 (s, 2H), 3.86 (s, 2H),3.30 (d, 1H), 3.15-2.98 (m, 3H), 2.76 (dd, 1H), 2.62 (dd, 1H), 2.50-2.41(m, 3H), 2.29 (dt, 1H), 2.12 (td, 1H), 1.92-1.86 (m, 1H), 1.63-1.54 (m,2H), 0.92-0.84 (m, 1H), 0.56 (q, 2H), 0.14 (q, 2H). [M+H]+ 604.16.

1.14 Compound 1i Synthesis of2-(5-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)naphthalen-1-yl)aceticAcid

To a suspension of 2,2′-(naphthalene-1,5-diyl)diacetic acid (350 mg,1.43 mmol) in tetrahydrofuran (36 mL) was added triethylamine (0.2 mL,1.43 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (744 mg, 1.43 mmol) and then naltrexone (489 mg,1.43 mmol). The resulting brown mixture was stirred at room temperature.After 18 hours the reaction mixture was concentrated and purified byreverse phase chromatography (C18) twice. Clean fractions were combinedand freeze-dried to give2-(5-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)naphthalen-1-yl)aceticacid as a white solid (120 mg, 15%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.97-7.90 (m, 2H), 7.56 (d, 1H), 7.53-7.47(m, 2H), 7.43 (d, 1H), 6.79 (d, 1H), 6.67 (d, 1H), 4.90 (s, 1H), 4.41(s, 2H), 4.01 (s, 2H), 3.13 (d, 1H), 3.02 (d, 1H), 2.88 (td, 1H),2.64-2.49 (m, 2H), 2.38-2.29 (m, 3H), 2.10 (td, 1H), 1.90 (dt, 1H),1.79-1.73 (m, 1H), 1.41 (dt, 1H), 1.23 (dd, 1H), 0.88-0.80 (m, 1H),0.49-0.40 (m, 2H), 0.13-0.05 (m, 2H) (COOH and OH protons are notobserved, contains 3.4% w/w of ammonium formate). [M+H]⁺ 568.29.

Example 2: Whole Blood Stability Assay

Naltrexone prodrug stability was assessed using freshly collected wholeblood (within 24-hr collection) from pooled human (n=3) donors. Theincubation mixtures were prepared by spiking the prodrugs intopre-warmed (37 degrees C.) fresh whole blood to a final concentration of50 nM. After gentle mixing, aliquots of incubation mixtures wereimmediately transferred into four different 96-deep well plates. Oneplate was used for each time point. The plates were incubated at 37degrees C. at a shaking speed of 100 rpm. At time points 15, 30, 60 and120 minutes, the reaction was quenched by addition of a mixture of waterand acetonitrile containing the internal standard (naltrexone-D₃). Timepoint 0 minutes was prepared separately by spiking the prodrugs into aquenched whole blood to obtain a final concentration of 50 nM. Allsamples were vortexed at a low speed for 15 min and centrifuged at 3900rpm for 15 min. Supernatants were transferred into 96-well plates forLC-MS/MS analysis to monitor the depletion of the prodrugs and theformation of naltrexone.

The amount of remaining prodrug and released naltrexone for each samplewas quantitated against the calibration curves prepared with the wholeblood. The human whole blood was purchased from BioreclamationIVT(Westbury, N.Y., USA). Naltrexone-D₃ was purchased from CERILLIANT®(Round Rock, Tex., USA). Table C shows the half-life of the prodrugs andthe amount of naltrexone (in equivalents) measured in whole blood at the2 hour timepoint. Where multiple runs have been completed, averagevalues are reported.

TABLE C t_(1/2) at 37 degrees Naltrexone formed C. in human whole inhuman whole blood Prodrug blood (min) at 2 hours (equiv.) Compound 126.4 1.18 Compound 2 20.9 1.58 Compound 3 14.8 1.24 Compound 4 28.9 1.44Compound 5 20.4 1.35 Compound 6 25.7 0.99 Compound 7 58.6 0.88 Compound8 26.3 1.18 Compound 9 40.9 1.43 Compound 10 14.7 1.60 Reference 54.70.78 Compound A

Reference Compound A is disclosed in Burce et al., Journal ofChromatography, 137 (1977), 323-332 as NTX-3-terephthaloyl-NTX.

Example 3: Pharmacokinetic Evaluation of the Release of Naltrexone fromCompound 2 in Rats Following a Single Intramuscular Injection

Five male Sprague-Dawley rats were allowed to acclimate to the testfacility for at least 2 days prior to study start. For doseadministration of Compound 2, the rats were lightly anesthetized withisofluorane, the hind leg shaved and dosed intramuscularly with theformulation using a 21G needle. All animals were observed at dosing andeach scheduled collection. Serial whole blood samples were collected viasublingual route (˜150 μL) at 1, 8, and 24 hours post dose, and at 2, 4,7, 10, 14, 17, 21, 24, 28, 35, 42, 49, 56, 63, 71, 78, 85, and 91 dayspost dose.

Blood samples were placed into K₂EDTA blood collection tubes. Aftercollection, blood samples were maintained chilled (on wet ice) andcentrifuged (11,500 rpm for 2 minutes at 5 degrees C.) within 30 minutesto obtain plasma. Plasma was transferred into a single vial, 1.5 mLscrew cap micro-centrifuge tube with inserts and stored at −80 degreesC. until analysis.

The formulation dosed was a crystalline suspension of Compound 2 (46milligrams of Compound 2 dosed per animal), wherein the crystalline testarticle was characterized with a particle size distribution ofD_(v10)=12.9 μm, D_(v50)=31.5 μm, and D_(v90)=63.1 μm (as measured vialaser diffraction). The formulation was prepared the day before dosing.Details of the formulation dosed are described in Table D below.

TABLE D Naltrexone Prodrug Dose Test Test Dose Level Conc. VolumeArticle Article (mg/kg) (mg/mL) (mL) Vehicle Storage Compound 2 186.01250.0 0.25 0.2% ambient (free base) polysorbate 20, pH 7, 10 mMphosphate buffer

Results of the above intramuscular rat study of Compound 2 are shown inTables E and F. In particular, Table E reports the average blood plasmalevels of naltrexone in rat (n=5) over 91 days following intramuscularadministration. As shown in Table E, the average blood plasma levels ofnaltrexone were at or above approximately 1 ng/mL over the 91 dayduration. Further, Table F shows the concentrations measured for parentCompound 2, and the resultant intermediate Compound 2i for each animal.As shown in Table F, the concentrations of parent Compound 2 and theresultant intermediate were generally low to not measurable (below thelimit of quantitation reported below). These data show efficientconversion of Compound 2 in rats to naltrexone over 91 days with minimalobserved plasma concentrations of the intact prodrug (i.e., Compound 2)or its resultant intermediate (i.e., Compound 2i).

TABLE E Days NTX conc. (ng/mL) Standard Deviation 0.042 (1 hour) 13.821.7  0.33 (8 hour) 3.18 1.5 1 1.37 0.12 2 1.92 0.57 4 1.99 0.75 7 1.810.46 10 1.80 0.98 14 1.03 0.13 17 1.18 0.25 21 1.21 0.41 24 1.19 0.34 280.98 0.25 35 1.09 0.29 42 1.18 0.40 49 1.26 0.59 56 1.31 0.77 63 1.370.78 71 1.50 0.82 78 1.54 0.82 85 1.40 0.89 91 1.42 0.84

TABLE F Compound 2 conc. (ng/mL)* Compound 2i conc. (ng/mL)* Days Rat 1Rat 2 Rat 3 Rat 4 Rat 5 Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 0.042 (1 hr) 0.2230.112 <0.1 0.131 0.113 <0.2 <0.2 <0.2 <0.2 <0.2  0.33 (8 hr) <0.1 <0.1<0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2<0.2 <0.2 <0.2 <0.2 2 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.24 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 7 <0.1 <0.1 0.175<0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 10 0.111 <0.1 0.104 0.119 <0.1 <0.2<0.2 <0.2 <0.2 <0.2 14 0.119 0.135 <0.1 0.144 0.136 <0.2 <0.2 <0.2 0.216<0.2 17 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 21 <0.1 <0.1<0.1 <0.1 3.25 <0.2 <0.2 <0.2 <0.2 <0.2 24 0.198 0.177 0.217 0.170 0.280<0.2 <0.2 <0.2 <0.2 <0.2 28 0.236 0.193 0.205 0.176 0.111 <0.2 <0.2 <0.2<0.2 <0.2 35 0.165 0.439 0.350 0.265 0.152 <0.2 <0.2 <0.2 <0.2 <0.2 420.155 0.156 0.212 0.199 0.205 <0.1 <0.1 <0.1 <0.1 <0.1 49 <0.1 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 56 0.358 0.205 0.105 0.170 0.163 <0.1<0.1 <0.1 <0.1 <0.1 63 <0.1 <0.1 <0.1 0.142 <0.1 <0.1 <0.1 <0.1 <0.1<0.1 71 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 78 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 85 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 91 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1*Values with a “<” sign indicate concentrations below the limit ofquantitation

Example 4: Characterization and Crystallization Method for Compound 2

Compound 2 was crystallized according to the following procedure. A 2 Lreactor was set up with a 50-50 water-glycol recirculator set to 90degrees C., preheating the jacket for 30 minutes. 1.768 grams ofCompound 2 was placed into an empty 2 L reactor. To the reactor, 520grams of isopropyl acetate was added and stirring started at 150 rpm.The solution was heated until all solids were fully solubilized. 810grams of heptane was then added immediately as a single addition. Thisslurry was held at 90 degrees C. for about ten minutes, at which pointthe heat was turned off, and reactor and jacket were cooled withoutassistance to room temperature over several hours. Solids formed andwere filtered by vacuum filtration.

FIG. 1 shows a powder x-ray diffraction (PXRD) pattern of thecrystalline form. The PXRD pattern was collected using a Rigaku MiniflexII Desktop X-ray diffractometer, with CuKα radiation at 15 mA and 30 kV.Each sample was mounted on a zero background sample holder. A scan speedof 7.5°/min 2-theta was chosen, coupled with a sampling width of 0.2°2-theta and a start and stop angle of 2 degrees and 40 degrees 2-theta.The crystalline form of Compound 2 can also be characterized by any one,any two, any three, any four, any five, or any six or more of the peaksin the PXRD diffractogram in FIG. 1 including, but not limited to, 7.34,9.40, 10.80, 11.83, 12.36, 12.94, 13.77, 14.70, 15.52, 17.77, 21.16, and23.76 degrees 2-theta (±0.2 degrees).

For example, in one embodiment, the crystalline form of Compound 2 canbe characterized by the PXRD peaks at 7.34, 9.40, 10.80, and 11.83degrees 2-theta (±0.2 degrees). In another embodiment, the crystallineform of Compound 2 can be characterized by the PXRD peaks at 10.80,11.83, 14.70 and 17.77 degrees 2-theta (±0.2 degrees). In anotherembodiment, the crystalline form of Compound 2 can be characterized bythe PXRD peaks at 9.40, 11.83, 12.36 and 13.77 degrees 2-theta (±0.2degrees).

Differential scanning calorimetry (DSC) was also performed on thecrystalline form of Compound 2. An endotherm was measured with an onsettemperature at 209.0 degrees C. and a melt temperature at 212.4 degreesC. The DSC thermogram was measured with a TA Instruments Q2000 DSC. Anapproximately 3-6 mg sample was accurately weighed into a hermetic pan.Dry nitrogen was used as a purge gas (50 mL/min nitrogen) and a heatingrate of 1 or 5 degrees C. min⁻¹ up to 300 degrees C. was applied.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed:
 1. A compound of Formula Ib:

or a pharmaceutically acceptable salt thereof; wherein: both R groups,always being the same, are selected from hydrogen, halogen,unsubstituted C₁-C₄ alkyl, unsubstituted C₁-C₄ alkoxy, or unsubstitutedC₁-C₄ alkylcarbonyloxy; both values of z, always being the same, are 1,2, 3, or 4; and wherein the R groups are bound with points of attachmentselected from the 1 and 1′ positions, the 3 and 3′ positions, or the 4and 4′ positions.
 2. The compound of claim 1, wherein the R groups arebound with points of attachment at the 1 and 1′ positions.
 3. Thecompound of claim 1, wherein the R groups are bound with points ofattachment at the 3 and 3′ positions.
 4. The compound of claim 1,wherein the R groups are bound with points of attachment at the 4 and 4′positions.
 5. The compound of claim 1, wherein both R groups arehydrogen.
 6. The compound of claim 1, wherein both R groups are halogen.7. The compound of claim 1, wherein both R groups are unsubstitutedC₁-C₄ alkyl.
 8. The compound of claim 1, wherein both R groups aremethyl.
 9. The compound of claim 1, wherein both R groups are methoxy.10. The compound of claim 1, wherein both R groups aremethylcarbonyloxy.
 11. The compound of claim 1, wherein both values of zare
 1. 12. The compound of claim 1, wherein both values of z are
 2. 13.A compound of claim 1 selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 15. The pharmaceutical composition of claim 14,wherein the composition is adapted for parenteral administration. 16.The pharmaceutical composition of claim 15, wherein the compositionprovides a duration of release of naltrexone of about 9 weeks followingparenteral administration.
 17. The pharmaceutical composition of claim15, wherein the composition provides a duration of release of naltrexoneof about 13 weeks following parenteral administration.
 18. Thepharmaceutical composition of claim 15, wherein the parenteraladministration is an intramuscular injection.